High purity copper radiopharmaceutical compositions and diagnostic and therapeutic uses thereof

Abstract

The present disclosure relates to the field of nuclear imaging and therapy, and more particularly, to high purity copper radiotracer compositions that can be used in imaging (e.g., positron emission tomography (PET) and single photon emission computed tomography (SPECT)) and therapy. More specifically, the present disclosure relates to novel compositions useful for imaging and treating conditions (e.g., prostate cancer, somatostatin receptor expressing tumors, such as neuroendocrine tumors, epithelial tumors), and methods of making such compositions.

Description

[0001] 1. Background

[0002] The present disclosure relates to a new class of radiotracers having the potential for "true theranostic" use, based on a new high-purity 6x Cu radionuclide production platform, which combines a cancer diagnostic agent and therapy with a single chemical entity meeting the requirements of an ideal positron emission tomography (PET) or single photon emission computed tomography (SPECT) tracer. More specifically, the present disclosure relates to novel constructs and their compositions and their use in imaging, diagnosing, and treating conditions such as myocardial infarction, interstitial lung disease, and cancer (including prostate cancer, epithelial tumors expressing FAP, and neuroendocrine tumors), as well as methods for making these compositions.

[0003] In nuclear medicine, radiotracers are used to diagnose and treat various conditions and diseases. A radiotracer is a compound in which a radionuclide is attached to a targeting moiety that targets a specific organ, cell, or biomarker in the human body.

[0004] Radiotracers can be used in targeted radionuclide therapy, using a targeting moiety that selectively localizes to malignant cells, tumors, or their associated microenvironment, and a radionuclide that is selected to emit low-range highly ionizing radiation (e.g., α or β - particles). The use of the same or similar biotargeting moieties that target specific biomarkers (e.g., cell surface receptors) to both diagnose and treat diseases in combination with different diagnostic and therapeutic radionuclides is called targeted theranostics. This approach overcomes the difficulty of quantifying the individual dose required for treatment through diagnosis, making the treatment of patients highly personalized. The use of radionuclides of the same element, e.g., copper radionuclides 60 Cu, 61 Cu, 62 Cu, and 64 Cu as positron emitters in diagnostic imaging and 67 Cu as an electron - emitter in radiotherapy can further improve the theranostic method, because radiotracers with different isotopes will bind to biomarkers identically.

[0005] The availability of a large portfolio of active and highly pure radiotracers is crucial for the development of nuclear medicine. Various copper radionuclides have been used in the field of nuclear medicine, and they provide diverse options for applications in radionuclide imaging (e.g., in radiotracers) and therapy.

[0006] Copper radionuclides, including 60 Cu, 61 Cu, 62 Cu, 64 Cu, and67 Cu provides versatile options for applications in imaging and therapy. Short-lived 60 Cu(t 1 / 2 = 23.4 min), 61 Cu(t 1 / 2 = 3.32 h), and 62 Cu(t 1 / 2 = 9.76 min) decay by electron capture and β + emission, and they have been used to prepare perfusion agents such as Cu-glyoxal bis(N 4 -methylthiosemicarbazone) (PTSM) and Cu-ethylglyoxal bis(thiosemicarbazone) ETS. Longer-lived 67 Cu(t 1 / 2 = 62.01 h) decays only by β - emission and has been used to label monoclonal antibodies and antibody fragments for radioimmunotherapy. 64 Cu has a medium half-life of 12.7 h and unique decay characteristics (β + : 18%, β - : 38%, and electron capture: 44%), making it useful for radiolabeling nanoparticles, antibodies, antibody fragments, peptides, and small molecules for PET imaging and radionuclide therapy. Therefore, 64 Cu radiopharmaceuticals can be used for quantitative PET imaging to calculate radiation dosimetry before targeted radiotherapy with 64 Cu or its β-emitting isotope configurational isomers 67 Cu. 64 Cu has been incorporated into many labeled radiotracers based on antibodies, peptides, and small molecules targeting specific receptors or antigens, especially in oncology applications.

[0007] Recently, 61 Cu(t 1 / 2 = 3.33 h, 61% β + , E max = 1.216 MeV) has been considered a better option for long-term imaging of processes with slower kinetics due to its longer half-life (3.33 h) compared to 60 Cu and 62 Cu. 61 Cu is a positron-emitting radionuclide with decay characteristics comparable to 68 Ga]Ga but with a lower maximum positron energy (E max = 1.216 MeV relative to E max= 1.899 MeV) and a significantly more practical half-life (3.33 h vs. 68 min). (McCarthy, D.W. et al. High-purity production and potential applications of copper-60 and copper-61. Nucl. Med. Biol. 1999, 26, 351–358.) The intermediate half-life and interesting decay characteristics allow for better image quality and potentially reduced radiation dose to the patient.

[0008] Radionuclides can be used in personalized medicine, but the quantity and quality supply for their clinical applications is a challenge. The production of target “disks” (usually disk-shaped objects with a target metal that is bombarded with subatomic particles to produce radionuclides) is crucial, and these target “disks” can produce radionuclide compositions with activities and the desired radionuclide purity at the end of bombardment (EoB), end of synthesis (EoB + 2 h), or at calibration. Appropriate target disk preparation is one of the most important aspects of cyclotron production of radionuclides.

[0009] Currently, PET is the only high-precision nuclear medicine imaging procedure capable of visualizing and measuring biochemical processes in cancer diagnosis. PET provides detailed information on disease progression that cannot be obtained by other imaging techniques or only via more invasive procedures. Although the effectiveness of radionuclides as PET tracers is beyond doubt, there are still significant obstacles to their widespread use, such as 1) high production costs (>400 euros or 400 US dollars / dose), 2) inflexible chemical processes (requiring complex and expensive radiochemical infrastructure), 3) limited distribution radius (short half-life), and 4) high radiation burden, putting patients at risk.

[0010] US2006 / 0004491 describes a functional automation method for separating and recovering 60 Cu, 61 Cu, and 64 Cu for the preparation of radiodiagnostic reagents (e.g., for PET imaging).

[0011] US10,975,089 relates to compounds allegedly useful as radiopharmaceuticals (e.g., radioimaging reagents) bearing radionuclide chelators for radiotherapy and diagnostic imaging. More specifically, compounds allegedly showing improved binding affinity to PSMA are described. According to US10,975,089, using amino acid-substituted ureas bound to macrocyclic sarcophagine via a specific linker provides compounds that bind to PSMA and provide improved imaging characteristics when complexed with radionuclides.

[0012] One object of the present disclosure is to provide compositions and methods that fully or partially overcome one or more of the problems recognized in the prior art, including radiopharmaceuticals, such as radiotracers, and their preparation.

[0013] 2. Overview

[0014] In a first aspect of the present disclosure, there is provided a compound comprising: a chelating moiety, optionally chelating a copper radionuclide ( * Cu), and a targeting moiety covalently linked to the chelating moiety.

[0015] In certain embodiments, there is provided a compound having the formula X:

[0016]

[0017] or a pharmaceutically acceptable salt thereof, wherein:

[0018] is the chelating moiety;

[0019] *Cu is optional and, if present, is selected from 61 Cu, 62 Cu, 64 Cu and 67 Cu;

[0020] L is a bond or a linking moiety;

[0021] V is the targeting moiety;

[0022] n is an integer from 1 to 10;

[0023] m is an integer from 1 to 10;

[0024] p is an integer from 1 to 10.

[0025] In certain embodiments, there is provided a compound having the formula A:

[0026]

[0027] In certain embodiments of the compound of formula X or formula A, the chelating moiety comprises 2-8 binding moieties. In certain embodiments, one or more of the binding moieties are selected from thiol groups, amine groups, and carboxylic acid groups.

[0028] In certain embodiments, the chelating moiety includes: 2,2',2''-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA); 2-(4,7-bis(carboxymethyl)-1,4,7-triazacyclononane-1-yl)succinic acid (NODASA); 2-(4,7-bis(carboxymethyl)-1,4,7-triazacyclononane-1-yl)glutaric acid (NODAGA); or 2,2'((2-(,7-bis-(carboxymethyl)-1,4,7-triazacyclononane-1-yl)ethyl)azanediyl)diacetic acid (NETA).

[0029] In certain embodiments, the targeting moiety is recognized by a molecular target expressed on malignant cells or pre-malignant cells, cells in the tumor microenvironment, inflammatory tissue, or tissue remodeling sites in myocardial infarction or interstitial lung disease fibrosis sites.

[0030] In a second aspect of the present disclosure, there is provided a composition comprising a compound which is a compound of formula X or formula A or a pharmaceutically acceptable salt thereof. Preferably, the composition has a radiochemical purity of ≥91% or a molar activity of 1 to 250 MBq / nmol. In certain embodiments, the composition has both a radiochemical purity of ≥91% and a molar activity within the range of 1 to 250 MBq / nmol.

[0031] In an exemplary embodiment, there is provided a compound, such as a novel 61 Cu radiotracer and its composition for (i) imaging, diagnosing, and staging cancer, such as: prostate cancer, cancers expressing somatostatin receptors, and epithelial cancers (e.g., using a 61 Cu]Cu-based radiotracer, such as 61 Cu]Cu-NODAGA-PSMA-I&T, 61 Cu]Cu-NODAGA-TOC, 61 Cu]Cu-NODAGA-LM3, 61 Cu]Cu-NODAGA-F1, 61 Cu]Cu-NODAGA-F2, 61 Cu]Cu-NODAGA-F3, and 61 Cu]Cu-NODAGA-F4). In a further contemplated embodiment, for (ii) targeted radionuclide therapy for cancers such as prostate cancer, cancers expressing somatostatin receptors, and epithelial cancers (e.g., using a 67 Cu-based radiotracer, such as 67 Cu]Cu-NODAGA-PSMA-I&T, 67 Cu]Cu-NODAGA-LM3,67 Cu]Cu-NODAGA-F1, 67 Cu]Cu-NODAGA-F2, 67 Cu]Cu-NODAGA-F3, and 67 Cu]Cu-NODAGA-F4.)

[0032] In a third aspect of the present disclosure, a method for generating an image of a subject is provided, the method comprising administering to the subject a composition according to the first aspect of the present disclosure; and generating an image of ≥ a part of the subject's body, for example using positron emission tomography (PET) or single photon emission computed tomography (SPECT). In certain embodiments, PET is used and *Cu is 61 Cu. In certain embodiments, SPECT is used and *Cu is 67 Cu.

[0033] In a fourth aspect of the present disclosure, a method for detecting a disease in a subject is provided, the method comprising administering to the subject a composition according to the first aspect of the present disclosure; detecting the localization of the radiotracer in the subject, for example using PET or SPECT. In certain embodiments, PET is used and *Cu is 61 Cu]Cu. In certain embodiments, SPECT is used and *Cu is 67 Cu.

[0034] In certain embodiments, the diseases to be detected include cancer, such as cancers expressing somatostatin receptors such as neuroendocrine tumors, prostate cancer, and malignant meningioma; epithelial cancers and their respective microenvironments that overexpress FAP, including non-small cell lung cancer, triple-negative breast cancer, colorectal cancer, gastric cancer, ovarian cancer, and pancreatic cancer; myocardial infarction; and interstitial lung disease.

[0035] In a fifth aspect of the present disclosure, a method for monitoring the effect of cancer treatment on a subject with cancer is provided, the method comprising administering to the subject a composition according to the first aspect of the present disclosure; and detecting the localization of the radiotracer in the subject, for example using PET or SPECT. In certain embodiments, PET is used and *Cu is 61 Cu]Cu. In certain embodiments, SPECT is used and *Cu is 67 Cu.

[0036] In a sixth aspect of the present disclosure, a method for providing radionuclide therapy to a cancer patient in need is provided, the method comprising administering to the subject a composition according to the first aspect of the present disclosure. In certain embodiments, *Cu is 67 Cu.

[0037] In a seventh aspect of the present disclosure, there is provided a method of treating cancer in a patient in need thereof, the method comprising administering to the subject a composition according to the first aspect of the present disclosure. In certain embodiments, *Cu is 67 Cu.

[0038] In certain embodiments of the fifth, sixth, and seventh aspects, the cancer is selected from: somatostatin receptor-expressing tumors such as neuroendocrine tumors, prostate cancer, and malignant meningioma; and epithelial cancers overexpressing FAP and their respective microenvironments, such as non-small cell lung cancer, triple-negative breast cancer, colorectal cancer, gastric cancer, ovarian cancer, and pancreatic cancer.

[0039] 3. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] These and other features, aspects, and advantages of the present disclosure will become better understood with reference to the following description and drawings, in which:

[0041] Figure 1 Shows a uniform nickel coating with persistent adhesion to the niobium target disk at the end of electroplating, as evaluated using a DINOLite digital microscope. Subfigure A, 20x magnification; subfigure B, 50x magnification; subfigure C, 250x magnification.

[0042] Figure 2 Shows a sample of the target disk provided according to the present disclosure, where nickel is deposited in the center of the niobium backing.

[0043] Figure 3 Shows the nat Ni3h obtained by irradiating the 61 Cu]CuCl2 solution on the Nb backing with a deuteron beam at 8.4 MeV at 50 μA. 61 Analysis of the 61 Cu purity. The curve corresponds to the decrease in the % purity of

[0044] Figure 4 Shows the 60 Ni3h obtained by irradiating the 61 Cu]CuCl2 solution on the Nb backing with a deuteron beam at 8.4 MeV at 50 μA. 61 Analysis of the 61 Cu purity. The curve corresponds to the decrease in the % purity of

[0045] Figure 5 Presents the 61The radioactive concentration of impurities detected in the Cu]CuCl2 solution. Existing (ext.) target disks (Ag, natNi) data were generated by irradiating commercially available nat Ni targets on an Ag backing. (Nb, natNi) and (Nb, Ni-61) data were generated based on irradiating Ni targets electroplated according to the present disclosure on a high-purity Nb backing (natural and 61 Ni isotope-enriched, respectively). The radioactive concentration was evaluated by gamma spectrometry and reported in Bq / g. The data indicate that in the 61 Cu]CuCl2 solution produced by irradiating Ni targets electroplated according to the present disclosure on a high-purity Nb backing, silver and cobalt isotopes are significantly reduced.

[0046] Figure 6 Shows a significant reduction in the sum of the radionuclide impurities present in the 61 Cu]CuCl2 solution produced according to various methods. Existing target disk (Ag, natNi) data were generated by irradiating commercially available nat Ni targets on an Ag backing. (Nb, natNi) and (Nb, Ni-61) data were generated based on irradiating Ni targets electroplated according to the present disclosure on a high-purity Nb backing (natural and 61 Ni isotope-enriched, respectively). The radionuclide impurities were determined by gamma spectrometry and reported in Bq / g (total radionuclide impurities). The presented data particularly highlight the reduction in the total impurities in the 61 Cu]CuCl2 solution produced according to the present disclosure.

[0047] Figure 7 Illustrates the consistently high radionuclide purity of the nat Cu]CuCl2 solution produced according to the present disclosure compared to commercially available 61 Ni targets on an Ag backing (existing target disk (Ag, natNi)). (Nb, natNi) and (Nb, Ni-61) target disks were prepared by electrodeposition according to the present disclosure on a high-purity Nb backing. The data were generated using gamma spectrometry and reported in Bq / g, providing the total radionuclide purity at t = 0 h and at t = 12 h. The presented data highlight that when producing the 61 Cu]CuCl2 solution by irradiating Ni targets electroplated according to the present disclosure on a high-purity Nb backing, the quality of the solution is excellent, where the purity is still far higher than the purity limit set by the pharmacopoeia for similar radionuclides for medical use after 12 hours.

[0048] Figure 8 Shows that when producing by irradiating Ni targets electroplated according to the present disclosure on a high-purity Nb backing, during bombardmentnat Ni relative to bombardment 61 When produced from Ni, 61 Chemical impurities in the Cu]CuCl2 solution (measured by ICP-MS).

[0049] Figure 9 , subfigures A - C, illustrate the IC by measuring various constructs 50 The affinity of each exemplary construct measured, as described in Example 5. Subfigures A and B show that between two nat Cu-complexed PSMA constructs (subfigure A) and two nat Cu-complexed TOC somatostatin constructs (subfigure B), the exchange of the chelator from DOTAGA (reference construct DOTAGA-PSMA-I&T used clinically) and DOTA (reference construct DOTA-TOC used clinically) to the chelator NODAGA (NODAGA-PSMA-I&T and NODAGA-TOC respectively) does not interfere nat with the affinity of the Cu-complexed constructs for their molecular targets (PSMA and SST2 respectively). Subfigure C shows that the complexation of Cu (or radiolabeling with 61 Cu) does not interfere with the affinity of the NODAGA-LM3 construct for its molecular target (SST2), and the IC nat values of NODAGA-LM3 and 50 Cu-NODAGA-LM3 remaining the same indicates this.

[0050] Figure 10 , subfigures A and B illustrate the 61 Cu]Cu-DOTAGA-PSMA-I&T (subfigure A) and 61 Cu]Cu-NODAGA-PSMA-I&T in PSMA-positive tumor-bearing mice within 1 hour obtained according to Example 8; L = liver; K = kidney; I = intestine; Bl = bladder; T = tumor; J = joint; SG = salivary gland.

[0051] Figure 11 , subfigures A and B illustrate the 61 Cu]Cu-NODAGA-PSMA-I&T and 61 Cu]Cu-DOTAGA-PSMA-I&T in PSMA-positive tumor-bearing mice at 1 hour and 4 hours after injection (subfigure A) and the time-activity curves of the tumor and kidney (subfigure B; circles are 61 Cu]Cu-NODAGA-PSMA-I&T and squares are61 Cu]Cu-DOTAGA-PSMA-I&T).

[0052] Figure 12 (Subfigures A - C) show the differentially chelated Cu 2+ ( 61 Cu]Cu-DOTAGA-PSMA-I&T (Subfigure A) vs. 61 Cu]Cu-NODAGA-PSMA-I&T (Subfigure B) vs. unchelated 61 Cu]CuCl2) in terms of biodistribution (1 to 4 hours).

[0053] Figure 13 , Subfigures A - F, show the dynamic PET / CT scans within 1 hour and static PET / CT scans at 4 hours after injection of 61 Cu]Cu-DOTA-TOC (Subfigures A and B), 61 Cu]Cu-NODAGA-TOC (Subfigures C and D) (obtained according to Example 8) and after injection of 61 Cu]Cu-NODAGA-LM3 (Subfigures E and F) in SST2-positive tumor-bearing mice.

[0054] Figure 14 , Subfigures A - C, illustrate the PET / CT scans at 1 hour in PSMA-positive tumor-bearing mice obtained according to Example 10 after single injection of the radiotracer or injection of the blocking agent 2-PMPA for 61 Cu]Cu-NODAGA-PSMA-I&T (Subfigure A) and 61 Cu]Cu-DOTAGA-PSMA-I&T (Subfigure B) and the PET / CT scan of 61 Cu]CuCl2 (Subfigure C) at 1 hour.

[0055] Figure 15 , Subfigures A - B illustrate the dynamic PET / CT scans within 1 hour of HT1080.hFAP and HT1080.wt dual-tumor-bearing mice for 61 Cu]Cu-NODAGA-F1 (Subfigure A) and 61 Cu]Cu-NODAGA-F3 (Subfigure B).

[0056] Figure 16 , Subfigures A - D, show at 1 hour (Subfigure A) and 4 hours (Subfigure B) in mice bearing FAP-positive xenografts 61Cu]Cu-NODAGA-F1 and at 1 hour (subfigure C) and 4 hours (subfigure D) 61 Static PET / CT scans of Cu]Cu-NODAGA-F3.

[0057] Figure 17 Showed 61 Cu-labeled and 68 Ga-labeled conjugates' partition coefficients (logD PBS / 辛醇，pH＝7.4 ). From left to right: 61 Cu]Cu-NODAGA-F1, 61 Cu]Cu-NODAGA-F3, 61 Cu]Cu-NODAGA-F2, 61 Cu]Cu-NODAGA-F4, 68 Ga]Ga-FAPI-46 and 61 Cu]Cu-NODAGA-FAPI-46.

[0058] Figure 18 Showed nat Cu]Cu-NODAGA-F1, nat Cu]Cu-NODAGA-F3, nat Cu]Cu-NODAGA-F2 and nat Cu]Cu-NODAGA-F4's inhibition (IC 50 ).

[0059] Figure 19 , subfigures A - D, showed 61 Cu]Cu-NODAGA-F1 (subfigure A), 61 Cu]Cu-NODAGA-F3 (subfigure B), 61 Cu]Cu-NODAGA-F2 (subfigure C) and 61 Cu]Cu-NODAGA-F4 (subfigure D)'s cell surface (cell membrane binding) and internalized fractions of cellular uptake. The values are expressed as a percentage of the applied activity and refer to the specific uptake calculated by subtracting the non-specific value (measured in the presence of the non-FAP expressing cell line HT-1080.wt) from the total value (specific = total - non-specific).

[0060] Figure 20 Showed 61Cell uptake of the cell surface (membrane-bound) and internalized fractions of [Cu]Cu-NODAGA-FAPI-46. The values are expressed as percentages of the applied activity and refer to the specific uptake calculated by subtracting the non-specific values (measured in the presence of the non-FAP expressing cell line HT-1080.wt) from the total value (specific = total - non-specific).

[0061] Figure 21 Shows 61 [Cu]Cu-labeled conjugates, 61 [Cu]Cu-NODAGA-F1, 61 [Cu]Cu-NODAGA-F2, 61 [Cu]Cu-NODAGA-F3, 61 [Cu]Cu-NODAGA-F4, 61 Saturation binding of [Cu]Cu-NODAGA-FAPI-46 on isolated HEK-293-hFAP membranes.

[0062] Figure 22 , Panels A and B, show in HT-1080.hFAP tumor-bearing mice at 1 and 4 hours after administration 61 [Cu]Cu-NODAGA-FAPI-46 (Panel A) and 68 [Ga]Ga-FAPI-46 (Panel B) biodistribution profiles.

[0063] Figure 23 , Panels A and B, show in HT-1080.hFAP tumor-bearing mice at 1 and 4 hours after administration 61 [Cu]Cu-NODAGA-FAPI-46 (Panel A) and 68 [Ga]Ga-FAPI-46 (Panel B) tumor-to-organ ratios.

[0064] Figure 24 , Panels A and B, show in HT-1080.hFAP tumor-bearing mice at 1 and 4 hours after administration 61 [Cu]Cu-NODAGA-F1 (Panel A) and 61 [Cu]Cu-NODAGA-F3 (Panel B) biodistribution profiles.

[0065] Figure 25 , Panels A and B, show in HT-1080.hFAP tumor-bearing mice at 1 and 4 hours after administration 61 [Cu]Cu-NODAGA-F2 (Panel A) and 61Bio-distribution profiles of [Cu]Cu-NODAGA-F4 (Panel B).

[0066] Figure 26 , Panels A and B, showing in HT-1080.hFAP tumor-bearing mice at 1 hour and 4 hours after administration 61 [Cu]Cu-NODAGA-F1 (Panel A) and 61 [Cu]Cu-NODAGA-F3 (Panel B) tumor-to-organ ratios.

[0067] Figure 27 , Panels A and B, showing in HT-1080.hFAP tumor-bearing mice at 1 hour and hour after administration 61 [Cu]Cu-NODAGA-F2 (Panel A) and 61 [Cu]Cu-NODAGA-F4 tumor-to-organ ratios (Panel B).

[0068] Figure 28 , Panels A and B, showing in mice bearing FAP-positive xenografts 61 [Cu]Cu-NODAGA-F2 (Panel A) and 61 [Cu]Cu-NODAGA-F4 (Panel B) dynamic PET / CT scans.

[0069] Figure 29 , Panels A and B, showing in mice bearing FAP-positive xenografts 61 [Cu]Cu-NODAGA-FAPI-46 (Panel A) and 68 [Ga]Ga-FAPI-46 (Panel B) dynamic PET / CT scans.

[0070] Figure 30 , Panels A and B, showing 61 [Cu]Cu-NODAGA-F2 vs. 61 [Cu]Cu-NODAGA-F4 (1h and 4h) (Panel A) and 61 [Cu]Cu-NODAGA-FAPI-46 vs. 68 [Ga]Ga-FAPI-46 (1h and 4h for 61 [Cu]Cu-NODAGA-FAPI-46, 1h only for 68 [Ga]Ga-FAPI-46) (Panel B) SUV PET imaging.

[0071] Figure 31 Showing in a mouse model 61Cu]Cu-NODAGA-PSMA-I&T (1 hour and 4 hours) and at 1 hour 68 Ga]Ga-PSMA-11 distribution.

[0072] Figure 32A -C provided the 1 H-NMR data of NODAGA-PSMA-I&T. Figure 32A showed 1 the Figure 32B H-NMR spectrum, Figure 32C and

[0073] Figure 33 showed the 61 Cu]Cu-NODAGA-LM3 distribution after 1 hour and 4 hours, the images taken by PET / CT, compared with the 68 Ga]Ga-DOTA-TOC distribution, the images taken by PET.

[0074] Figure 34 showed after 1 hour 61 Cu]Cu-NODAGA-LM3 and 68 Ga]Ga-DOTA-TOC compound distribution in multiple organs.

[0075] Figure 35 , subfigures A-E showed the PET / CT images and planar scintigraphy of a 48-year-old patient with metastatic castration-resistant prostate cancer who had disease progression after receiving abiraterone and docetaxel treatment and was planned to receive 61 Cu]Cu-NODAGA-PSMA-I&T treatment. The patient was also in the state after left nephrectomy. The maximum intensity projection image (subfigure A) showed strong tracer uptake in multiple bone, pelvic lymph nodes and liver metastases. Transverse slices of the liver by PET (subfigure B), fused PET and CT (subfigure B) and CT (subfigure C) showed two PSMA-positive liver lesions with local tracer uptake. Non-contrast-enhanced CT image (subfigure D). The planar anterior image and post-treatment image 24 hours after administration of 177 Lu]Lu-PSMA-I&T showed a radioactive distribution similar to that of the PET image (subfigure E).

[0076] Figure 36 , subfigures A and subfigure B, showed in mice bearing SST2-positive xenograft tumors 61 Cu]Cu-(R)-NODAGA-LM3 (subfigure A) and 61Dynamic PET / CT scan of [Cu]Cu-NODAGA-LM3 (Subfigure B). Static images at 240 minutes are also presented.

[0077] Figure 37 Shows 61 Saturation binding of [Cu]Cu-NODAGA-LM3. Bmax ranges from 0.2082 to 0.2711 nM, k D ranges between 1.409 and 2.917 nM.

[0078] 4. Detailed Description

[0079] 4.1 Definitions

[0080] When describing embodiments of the present disclosure, which include compounds and their pharmaceutically acceptable salts, pharmaceutical compositions containing the compounds, and methods of using the compounds and compositions, unless otherwise indicated, the following terms (if any) have the following meanings.

[0081] Those skilled in the art will understand that, generally speaking, in this application, especially in the appended claims (e.g., the subject matter of the appended claims), the terms used are generally intended to be "open" terms (e.g., the term "comprising" should be construed as "including but not limited to", the term "having" should be construed as "having at least", the term "including" should be construed as "including but not limited to", etc.). Those skilled in the art will also understand that if a specific number of the introduced claim recitations is intended, such intention will be clearly recited in the claim, and if there is no such recitation, there is no such intention. For example, for the sake of understanding, the following appended claims may contain the use of introductory phrases such as "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed as implying that introducing a claim recitation by the indefinite article "a" or "an" will limit any particular claim containing such introduced claim recitation to an embodiment containing only one such recitation, even if the same claim includes an introductory phrase such as "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be construed as "at least one" or "one or more"); the same is true for the use of the definite article to introduce a claim recitation. In addition, even if a specific number of the introduced claim recitations is clearly recited, those skilled in the art will recognize that such recitation should be construed to mean at least the recited number (e.g., in the absence of other modifiers, a simple recitation of "two recitations" means at least two recitations, or two or more recitations). In addition, in cases where a convention similar to "at least one of A, B, and C, etc." is used, it is generally intended that the meaning of such construction is such that those skilled in the art can understand the convention (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, a system having A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In cases where a convention similar to "at least one of A, B, or C, etc." is used, it is generally intended that the meaning of such construction is such that those skilled in the art can understand the convention (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, a system having A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). Those skilled in the art will also understand that, whether in the specification, the claims, or the drawings, in fact any disjunctive word and / or phrase representing two or more alternative terms should be understood to contemplate the possibility of including one of the said terms, either of the said terms, or both terms. For example, the phrase "A or B" should be understood to include the possible cases of "A" or "B" or "A and B".

[0082] In addition, if the features or aspects of the present disclosure are described in the form of a Markush group, those skilled in the art will recognize that the present disclosure is also thereby described in terms of any individual member or subgroup of members of that Markush group.

[0083] Those skilled in the art will understand that for any and all purposes, such as in providing a written description, all ranges disclosed in this application also cover any and all possible sub-ranges and combinations of those sub-ranges. Any recited range can be readily regarded as fully described and enables the same range to be divided into at least equal halves, thirds, quarters, fifths, tenths, etc. By way of non-limiting example, each range discussed in this application can be readily divided into a lower third, middle third, and upper third, etc. Those skilled in the art will also understand that all language such as "at most", "at least", "greater than", "less than", etc. includes the recited numbers and refers to ranges that can then be divided into sub-ranges as described above. Finally, those skilled in the art will understand that a range includes each individual member. Thus, for example, a group having 1 - 3 items refers to a group having 1, 2, or 3 items. Similarly, a group having 1 - 5 items refers to a group having 1, 2, 3, 4, or 5 items, and so on.

[0084] The term "alkyl" as used in this application refers to straight-chain and branched C1-C 30 hydrocarbons, including saturated and unsaturated hydrocarbons. Use of names such as for example "C1-C 20 " is intended to refer to an alkyl group having the recited number of carbon atoms (e.g., straight-chain or branched, including olefins and alkyls). In certain embodiments, the alkyl group has 1 to 10 carbon atoms ("C1–C 10 alkyl"). In certain embodiments, the alkyl group has 1 to 9 carbon atoms ("C1–C9 alkyl"). In certain embodiments, the alkyl group has 1 to 8 carbon atoms ("C1–C8 alkyl"). In certain embodiments, the alkyl group has 1 to 7 carbon atoms ("C1–C7 alkyl"). In certain embodiments, the alkyl group has 1 to 6 carbon atoms ("C1–C6 alkyl"). In certain embodiments, the alkyl group has 1 to 5 carbon atoms ("C1–C5 alkyl"). In certain embodiments, the alkyl group has 1 to 4 carbon atoms ("C1–C4 alkyl"). In certain embodiments, the alkyl group has 1 to 3 carbon atoms ("C1–C3 alkyl"). In certain embodiments, the alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"). In certain embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). C 1–6Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, etc. Representative straight-chain alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc.; saturated branched-chain alkyl groups include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, etc.; representative saturated cyclic alkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0085] As used herein, the term "alkenyl" refers to a straight-chain or branched-chain hydrocarbon-based group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C2–C 20 alkenyl"). In certain embodiments, the alkenyl does not contain any triple bonds. In certain embodiments, the alkenyl has from 2 to 10 carbon atoms ("C2–C 10 alkenyl"). In certain embodiments, the alkenyl has from 2 to 9 carbon atoms ("C2–C9 alkenyl"). In certain embodiments, the alkenyl has from 2 to 8 carbon atoms ("C2–C8 alkenyl"). In certain embodiments, the alkenyl has from 2 to 7 carbon atoms ("C2–C7 alkenyl"). In certain embodiments, the alkenyl has from 2 to 6 carbon atoms ("C2–C6 alkenyl"). In certain embodiments, the alkenyl has from 2 to 5 carbon atoms ("C2–C5 alkenyl"). In certain embodiments, the alkenyl has from 2 to 4 carbon atoms ("C2–C4 alkenyl"). In certain embodiments, the alkenyl has from 2 to 3 carbon atoms ("C2–C3 alkenyl"). In certain embodiments, the alkenyl has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). C 2–4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. C 2–6 Examples of alkenyl groups include the above C 2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octatrieneyl (C8), etc.

[0086] As used herein, the terms "alkylene", "alkenylene", and "alkynylene" refer to divalent groups of alkyl, alkenyl, or alkynyl, respectively. When a range or number of carbons is provided for a particular "alkylene", "alkenylene", or "alkynylene", it is to be understood that the range or number refers to the range or number of carbons in the straight-chain carbon divalent chain. The "alkylene", "alkenylene", and "alkynylene" groups may or may not be substituted with one or more substituents described herein.

[0087] As used herein, the term "aryl" refers to an aromatic group having six to ten carbon atoms in the ring portion (e.g., monocyclic, bicyclic, and tricyclic structures). The aryl group may optionally be substituted through available carbon atoms and may contain one or more heteroatoms, such as oxygen, nitrogen, or sulfur, in certain embodiments. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C 10 aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl).

[0088] As used herein, "halo" and "halogen" refer to atoms selected from fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br), and iodine (iodo, I).

[0089] As used herein, "heteroaryl" refers to a group of 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring systems (e.g., sharing 6 or 10 electrons in a cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, when the valence allows, the point of attachment may be a carbon or nitrogen atom. The bicyclic heteroaryl system may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclic or heterocyclic groups, where the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, where the point of attachment is on the aryl or heteroaryl ring, and in such cases, the number of ring members represents the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl groups in which one ring contains no heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment may be on either ring, i.e., on the ring with heteroatoms (e.g., 2-indolyl) or on the ring without heteroatoms (e.g., 5-indolyl).

[0090] As used herein, the term "heterocyclic group" or "heterocycle" refers to a group of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, when the valence allows, the point of attachment can be a carbon or nitrogen atom. The heterocyclic group can be monocyclic ("monocyclic heterocyclic group") or a fused, bridged, or spiro ring system, such as a bicyclic system ("bicyclic heterocyclic group"), and can be saturated or can be partially unsaturated. The bicyclic heterocyclic group system can contain one or more heteroatoms in one or two rings. "Heterocyclic group" also includes a ring system in which a heterocyclic group ring as defined above is fused to one or more carbocyclic groups, wherein the point of attachment is on the carbocyclic group ring or the heterocyclic group ring, or a ring system in which a heterocyclic group ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclic group ring, and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclic group ring system. The terms "heterocycle", "heterocyclic group", "heterocyclic group ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic group" are used interchangeably. Heterocycles include morpholino, pyrrolidone, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothienyl, tetrahydrothiopyranyl, etc.

[0091] As used herein, the term "substituted", whether or not preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., a hydrogen attached to a carbon atom or a nitrogen atom of the group) is replaced by a permitted substituent, e.g., a substituent that results in a stable compound, e.g., a compound that does not undergo spontaneous transformation, such as by rearrangement, cyclization, elimination, or other reactions. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents at each position are the same or different.

[0092] When a numerical range is listed, it is intended to cover each numerical value and sub-range within that range. For example, "C1–C6 alkyl" is intended to cover C1, C2, C3, C4, C5, C6, C1–C6, C1–C5, C1–C4, C1–C3, C1–C2, C2–C6, C2–C5, C2–C4, C2–C3, C3–C6, C3–C5, C3–C4, C4–C6, C4–C5, and C5–C6 alkyls.

[0093] In typical embodiments, the present disclosure is intended to cover the compounds disclosed in the present application, as well as pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomeric forms, polymorphs, and prodrugs of such compounds. In certain embodiments, the present disclosure includes pharmaceutically acceptable addition salts, pharmaceutically acceptable esters, solvates (e.g., hydrates) of addition salts, tautomeric forms, polymorphs, enantiomers, enantiomeric mixtures, stereoisomers, or mixtures of stereoisomers (pure or as racemic or non-racemic mixtures) of the compounds described in the present application.

[0094] The compounds described in the present application may contain one or more asymmetric centers and may thus exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described in the present application may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be separated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw–Hill, New York, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions at page 268 (ed. by EL Eliel, University of Notre Dame Press, Notre Dame, Indiana, 1972). The present disclosure further covers the compounds described in the present application as individual isomers substantially free of other isomers, or, as mixtures of various isomers.

[0095] For chemical structures containing chelated metals, the structures drawn are not intended to define the coordination layer. In addition, the presence or absence of protons on ionizable binding moieties is not intended to be determinative. Those skilled in the art will be able to determine the coordination layer, oxidation state, and degree of ionization based on the specific circumstances.

[0096] 4.2 Compounds

[0097] One aspect of the present disclosure is to provide compounds comprising one or more chelating moieties and one or more targeting moieties covalently linked by L, where L is a bond or a divalent or polyvalent linking moiety, and optionally comprising a copper radionuclide (*Cu). In embodiments comprising a copper radionuclide, the compounds are considered "radioactively labeled" for diagnostic and / or therapeutic applications. These compounds are also referred to herein as "targeted chelator constructs" and are precursors of radioactively labeled compounds, which are also referred to as "radiotracers". It should be understood in the present application that when a particular compound (e.g., a radiotracer) is described in the present application as comprising a particular radioisotope or radionuclide (e.g., 61 Cu), the compound is enriched with that isotope at the indicated position.

[0098] The terms radioactive copper (also referred to herein as Cu*), copper radionuclide, and copper radionuclides are used interchangeably in the present application and refer to copper isotopes that undergo spontaneous radioactive decay.

[0099] Embodiments of the compounds disclosed in the present application comprise radioactive copper selected from: 60 Cu, 61 Cu, 62 Cu, 64 Cu, and 67 Cu. In certain embodiments, the radioactive copper is selected from 61 Cu, 64 Cu, and 67 Cu. In certain embodiments, the radioactive copper is 61 Cu]Cu. In certain embodiments, the radioactive copper is 67 Cu.

[0100] Certain embodiments of the radiotracers disclosed in the present application include radioactive copper (Cu*), wherein *Cu is in the (II) oxidation state.

[0101] In embodiments of the present disclosure, the provided compounds comprise one or more chelating moieties and one or more targeting moieties, the targeting moieties being covalently linked to the one or more chelating moieties by L, where L is a bond or a divalent or polyvalent linking moiety, and optionally including a copper radionuclide (*Cu).

[0102] In certain embodiments, there is provided a compound, wherein the compound has formula X:

[0103]

[0104] or a pharmaceutically acceptable salt thereof,

[0105] wherein:

[0106] is a chelating moiety;

[0107] L is a bond or linker moiety that connects said chelating moiety to a targeting moiety;

[0108] V is the targeting moiety;

[0109] n is an integer selected from 1 to 10;

[0110] m is an integer selected from 1 to 10; and

[0111] p is an integer selected from 1 to 10.

[0112] In certain embodiments, the provided compound has formula X*:

[0113]

[0114] or a pharmaceutically acceptable salt thereof,

[0115] wherein:

[0116] is a chelating moiety;

[0117] *Cu is selected from: 61 Cu, 62 Cu, 64 Cu and 67 Cu;

[0118] L is a bond or linker moiety that connects said chelating moiety to a targeting moiety;

[0119] V is the targeting moiety;

[0120] n is an integer selected from 1 to 10;

[0121] m is an integer selected from 1 to 10; and

[0122] p is an integer selected from 1 to 10.

[0123] In certain embodiments of the compound of formula X, p is an integer from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, or 1 to 9. In certain embodiments, p is an integer from 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, or 2 to 9. In certain embodiments, p is an integer from 3 to 5, 3 to 7, 5 to 7, 5 to 10, or 7 to 10. In certain embodiments, p is 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, p is 2, 3, or 4. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4.

[0124] In certain embodiments of the compound of formula X, m is an integer from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, or 1 to 9. In certain embodiments, m is an integer from 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, or 2 to 9. In certain embodiments, m is an integer from 3 to 5, 3 to 7, 5 to 7, 5 to 10, or 7 to 10. In certain embodiments, m is 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, m is 2, 3, or 4. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4.

[0125] In certain embodiments of the compound of formula X, n is 1, m is 2 and p is 2, such that the chelating moiety is polyvalent, such that 2 L moieties link 2 V targeting moieties to a divalent chelator. In certain embodiments of the compound of formula X, n is 1, m is 3 and p is 3, such that the chelating moiety is polyvalent, such that 3 L moieties link 3 V targeting moieties to a trivalent chelator. In certain embodiments, each L moiety is the same. In certain embodiments, at least one of the L moieties is different. In certain embodiments, each of the V moieties is the same. In certain embodiments, at least one of the V moieties is different.

[0126] In certain embodiments of the compound of formula X, n is 1, m and p are each the same integer and greater than 1, for example an integer from 2 to 10, wherein the chelating moiety is polyvalent. In certain embodiments, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, m is an integer from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, or 1 to 9. In certain embodiments, m is an integer from 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, or 2 to 9. In certain embodiments, m is an integer from 3 to 5, 3 to 7, 5 to 7, 5 to 10, or 7 to 10.

[0127] In certain embodiments of the compound of formula X, where formula X is understood herein to include sub-formula X1, n is 1, m is 1, p is 1, and L is divalent and connects the chelating moiety to the targeting moiety. In certain embodiments, where n is greater than 1, for example an integer from 2 to 10, L is multivalent and connects one or more chelating moieties to the targeting moiety. In certain embodiments, where n is 1, m is 2, p is 2, the chelating moiety is multivalent (e.g., divalent), and each of the two linking moieties (L) connects each of the two targeting moieties (V) to the divalent chelator. In certain embodiments, where n is 1, m is 3, p is 3, the chelating moiety is multivalent, and each of the three linking moieties (L) connects each of the three targeting moieties (V) to the trivalent chelator. In certain embodiments, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, m is an integer from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, or 1 to 9. In certain embodiments, m is an integer from 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8, or 2 to 9. In certain embodiments, m is an integer from 3 to 5, 3 to 7, 5 to 7, 5 to 10, or 7 to 10.

[0128] In certain embodiments of the compound of formula X, n is 1, m is 2, and p is 2, and each L is divalent and connects each of the two targeting moieties to the chelating moiety. In certain embodiments, n is 1, m is 1, p is 3, and L is multivalent and connects three targeting moieties (V) to the chelating moiety. In certain embodiments, n is 1, m is 1, and p is 4, and L is multivalent and connects each of the four targeting moieties to the chelating moiety.

[0129] In certain embodiments, the radioactive copper is selected from 61 Cu, 64 Cu, and 67 Cu, particularly 61 Cu or 67 Cu.

[0130] Some embodiments of the radiotracers disclosed herein include radioactive copper (Cu*), where *Cu is in the (II) oxidation state.

[0131] In certain embodiments, the compound is as shown in formula A:

[0132]

[0133] or a pharmaceutically acceptable salt thereof, wherein: is the chelating moiety;

[0134] L is a bond or a linking moiety that connects the chelating moiety to the targeting moiety;

[0135] V is the targeting moiety;

[0136] n is an integer selected from 1 to 10.

[0137] In certain embodiments, the compound conforms to Formula A*:

[0138]

[0139] or a pharmaceutically acceptable salt thereof, wherein: is a chelating moiety;

[0140] *Cu is optional and, if present, is selected from: 61 Cu, 62 Cu, 64 Cu or 67 Cu;

[0141] L is a bond or a linking moiety that links the chelating moiety to the targeting moiety;

[0142] V is the targeting moiety;

[0143] n is an integer selected from 1 to 10.

[0144] In certain embodiments of the compounds of Formulas X, X*, A and A*, n is an integer from 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8 or 1 to 9. In certain embodiments, n is an integer from 2 to 3, 2 to 4, 2 to 5, 2 to 6, 2 to 7, 2 to 8 or 2 to 9. In certain embodiments, n is an integer from 3 to 5, 3 to 7, 5 to 7, 5 to 10 or 7 to 10. In certain embodiments, n is 2, 3, 4, 5, 6, 7, 8, 9 or 10. In certain embodiments, n is 2, 3 or 4. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In the examples, n is 3. In certain embodiments, n is 4.

[0145] 4.2.1. Chelating moiety

[0146] The chelating moiety includes two or more binding moieties that can form multiple bonds with a single metal ion. The chelating moiety according to the present disclosure (represented by the symbol, where the lines show the points of attachment) is not particularly limited.

[0147] In certain embodiments of the compounds of Formula X, X*, A, and A*, the chelating moiety is selected from any copper chelator known in the art. In certain embodiments, the chelating moiety is capable of complexing with Cu(II) with relatively fast coordination kinetics, high biological stability, and inertness. Known chelating moieties can be modified, derivatized, or otherwise functionalized to facilitate covalent attachment to one or more targeting moieties, optionally via one or more linker moieties. In certain embodiments, one or more linker moieties are used to facilitate covalent attachment between the chelating moiety and one or more targeting moieties.

[0148] In embodiments of the present disclosure, the term chelating moiety generally encompasses both coordinated and uncoordinated states. That is, the chelating moiety can chelate a metal and is considered coordinated to, for example, a copper radionuclide, or it can not chelate a metal, such as a copper radionuclide, and is considered uncoordinated. In certain embodiments, when the chelating moiety is coordinated to radioactive copper, the term "chelated copper complex" is used in this application.

[0149] In certain embodiments of the compounds of Formula X, X*, A, and A*, the chelating moiety includes a binding moiety, i.e., a chemical group (e.g., one to ten atoms, such as the three atoms of a carboxylic acid group) that aids in binding a metal ion to form a coordination complex. In some instances, the binding moiety is capable of forming ionic, covalent, and / or coordination bonds. In certain embodiments, the chelating moiety includes 2 - 8 binding moieties. In certain embodiments, the chelating moiety includes 4, 5, 6, 7, or 8 binding moieties. In certain embodiments, the chelating moiety includes 6 binding moieties.

[0150] In certain embodiments of the compounds of Formula X, X*, A, and A*, the binding moiety is selected from thiol groups, amine groups, and carboxylic acid groups. In certain embodiments, one or more of the binding moieties contain a tertiary amine. In further embodiments of these embodiments, ≥ three of the binding moieties contain a tertiary amine, e.g., where three tertiary amines form a cyclic ring around the metal center.

[0151] In certain embodiments of the compounds of formula X or A, the chelating moiety is selected from DOTAGA (1,4,7,10-tetraazacyclododecane,1-(pentanedioic acid)-4,7,10-triacetic acid), DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTASA (1,4,7,10-tetraazacyclododecane-1-(2-succinic acid)-4,7,10-triacetic acid), CB-DO2A (10-bis(carboxymethyl)-1,4,7,10-tetraazabicyclo[5.5.2]tetradecane), DEPA (7-[2-(bis-carboxymethylamino)-ethyl]-4,10-bis-carboxymethyl-1,4,7,10-tetraaza-cyclododecane-1-yl-acetic acid)), 3p-C-DEPA (2-[(carboxymethyl)][5-(4-nitrophenyl-1-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]pent-2-yl)amino]acetic acid)), TCMC (2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane), oxo-DO3A (1-oxa-4,7,10-triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid), p-NH2-Bn-Oxo-DO3A (1-oxa-4,7,10-tetraazacyclododecane-5-S-(4-aminobenzyl)-4,7,10-triacetic acid), TE2A ((1,8-N,N′-bis-(carboxymethyl)-1,4,8,11-tetraazacyclotetradecane), MM-TE2A, DM-TE2A, CB-TE2A (4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2) hexadecane), CB-TE1A1P (4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid), CB-TE2P (1,4,8,11-tetraazacyclotetradecane-1,8-bis(methanephosphonic acid)), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), NOTA (1,4,7-triazacyclononane-N,N′,N″-triacetic acid), NODA (1,4,7-triazacyclononane-1,4-diacetate), NODAGA (1,4,7-triazacyclononane-1-pentanedioic acid-4,7-diacetic acid) (also known as NOTAGA), NODA desferrioxamine (1,4,7-triazacyclononane-1,4-diyl)diacetic acid DFO), NETA ([4-[2-(bis(carboxymethyl)amino)-ethyl]-7-carboxymethyl-[1,4,7]triazacyclononane-1-yl}-acetic acid), TACN-TM (N,N',N”, tris(2-mercaptoethyl)-1,4,7-triazacyclononane), DiamSar (1,8-diamino-3,6,10,13,16,19-hexaazabicyclo(6,6,6)icosane, 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1,8-diamine), Sarar (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1,8-diamine), AmBaSar (4-((8-amino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1-ylamino)methyl)benzoic acid) and 4,4'-((3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1,8-diylbis(azanediyl))bis(methylene))dibenzoic acid (BaBaSar).

[0152] In certain embodiments of the compounds of formulas X, X*, A and A*, the chelating moiety is selected from DOTAGA, DOTA, NOTA, NODAGA and NODA.

[0153] In certain embodiments of the compounds of formulas X, X*, A and A*, the chelating moiety is NODAGA. In certain embodiments of the compounds of formula A, the chelating moiety is R-NODAGA. In certain embodiments of the compounds of formula X or A, where L is a bond, the chelating moiety is NODAGA.

[0154] In further embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety comprises a structure selected from those shown below, it being noted that these structures may also be considered to include a linker moiety. There is some flexibility as to which atoms comprise the chelating moiety and which atoms comprise the linker for attaching the chelating moiety to one or more targeting ligands. For example, the chelating moiety of the embodiments of the invention shown below may comprise a complete amide group (–(C=O)NH–), or it may comprise only the carbonyl group –(C=O)– such that –NH– (if present) is considered part of the linking group:

[0155]

[0156]

[0157]

[0158]

[0159] In certain embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety comprises: 2,2',2''-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA); 2-(4,7-bis(carboxymethyl)-1,4,7-triazacyclononan-1-yl)succinic acid (NODASA); 2-(4,7-bis(carboxymethyl)-1,4,7-triazacyclononan-1-yl)glutaric acid (NODAGA); or 2,2'((2-(,7-bis-(carboxymethyl)-1,4,7-triazacyclononan-1-yl)ethyl)azanediyl)diacetic acid (NETA). In certain embodiments, the chelating moiety comprises derivatives of these moieties, such as functional derivatives and derivatives that allow covalent attachment of the linker moiety.

[0160] In certain embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety comprises NOTA. In certain embodiments, the chelating moiety comprises NODASA. In certain embodiments, the chelating moiety comprises NODAGA. In certain embodiments, the chelating moiety comprises NETA.

[0161] In certain embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety comprises: DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTAGA (1,4,7,10-tetraazacyclododecane,1-(glutaric acid)-4,7,10-triacetic acid), HBED, HBED-CC TFP or H2DEDPA, as shown below. In certain embodiments, the chelating moiety comprises derivatives of these moieties, such as functional derivatives and derivatives that allow covalent attachment of the linker moiety.

[0162]

[0163] In certain embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety comprises DOTA. In certain other embodiments, the chelating moiety comprises DOTAGA. In certain embodiments, the chelating moiety comprises derivatives of these moieties, such as functional derivatives and derivatives that allow covalent attachment of the linker moiety.

[0164] In certain embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety is selected from structures chosen from NOTA, NODAGA, NODASA, DOTA, DOTAGA or DOTASA, such as the structures shown in the immediately following table, which show a single point of attachment to the targeting moiety, optionally via a linker moiety. Embodiments are also contemplated in which each of the illustrated chelating moieties is further modified to a divalent or multivalent chelating moiety. In certain embodiments, one or more available carboxylic acid carbonyl carbons are points of attachment to a second targeting moiety and optionally a third targeting moiety (optionally via a linker moiety), thereby replacing a hydroxyl group. In certain embodiments, a methylene carbon is the point of attachment to a second targeting moiety and optionally a third targeting moiety (optionally via a linker moiety).

[0165]

[0166]

[0167] In certain embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety comprises a structure according to Formula 1:

[0168]

[0169] wherein:

[0170] R 1 、R 2 and R 3 are each independently C 2-6 alkyl, optionally substituted with one or more substituents selected from oxo, mercapto, hydroxy, C 1-3 alkoxy, C 1-3 carboxy and C 1-3 alkylthio, including their deprotonated variants, depending on chelation to *Cu;

[0171] wherein at least one of R 1 、R 2 and R 3 comprises a point of attachment to a linker moiety (when L is a linker moiety) or to a targeting moiety (when L is a bond).

[0172] In certain embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety comprises a structure according to formula 1’:

[0173]

[0174] wherein:

[0175] R 1 、R 2 and R 3 are each independently C 2-6 alkyl, optionally substituted by one or more substituents selected from oxo, mercapto, hydroxy, C 1-3 alkoxy, C 1-3 carboxy and C 1-3 alkylthio, including their deprotonated variants, depending on chelation to *Cu;

[0176] wherein represents the point of attachment to the linker moiety (when L is the linker moiety) or to the targeting moiety (when L is a bond).

[0177] In certain embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety comprises a structure according to formula 1’a

[0178]

[0179] In certain embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety comprises a structure according to formula 2:

[0180]

[0181] wherein X 1 、X 2 and X 3 are each independently selected from -OH, -NH2 and -SH, including their deprotonated variants, depending on chelation to *Cu;

[0182] wherein any methylene group is optionally substituted by oxo, mercapto or hydroxy; and

[0183] wherein represents the point of attachment to the linker moiety (when L is the linker moiety) or to the targeting moiety (when L is a bond).

[0184] In certain embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety comprises a structure according to formula 2’:

[0185]

[0186] wherein X 1 、X 2 and X 3Individually selected from -OH, -NH2, and -SH, including their deprotonated variants, depending on chelation with *Cu;

[0187] Wherein any methylene group is optionally substituted with oxo, mercapto, or hydroxy; and

[0188] Where Represents the point of attachment to the linker moiety (when L is the linker moiety) or to the targeting moiety (when L is a bond).

[0189] In certain embodiments of the compounds of formulas X, X*, A, and A*, the chelating moiety comprises a structure according to formula 2i, 2’i, 2ii, or 2iii:

[0190]

[0191] In certain embodiments of the compounds of formulas X, X*, A, and A*, the chelating moiety comprises a structure according to formula 2iR, 2’iR, or 2iiR:

[0192]

[0193] In certain embodiments of the compounds of formulas X, X*, A, and A*, the chelating moiety comprises a structure according to formula 3:

[0194]

[0195] Wherein:

[0196] R 1 、R 2 、R 3 And R 4 Are each independently C 2-6 Alkyl, optionally substituted with one or more substituents selected from oxo, mercapto, hydroxy, C 1-3 Alkoxy, C 1-3 Carboxy, and C 1-3 Alkylthio, including their deprotonated variants, depending on chelation with *Cu;

[0197] Where R 1 、R 2 、R 3 And R 4 At least one of which contains a point of attachment to the linker moiety (when L is the linker moiety) or to the targeting moiety (when L is a bond).

[0198] In certain embodiments of the compounds of formulas X, X*, A, and A*, the chelating moiety comprises a structure according to formula 3’:

[0199]

[0200] Wherein:

[0201] R 1 、R 2 、R 3 and R 4 is independently C 2-6 alkyl, optionally substituted with one or more substituents selected from oxo, mercapto, hydroxy, C 1-3 alkoxy, C 1-3 carboxy and C 1-3 alkylthio, including its deprotonated variants, depending on chelation to *Cu;

[0202] wherein represents the point of attachment to the linker moiety (when L is the linker moiety) or to the targeting moiety (when L is a bond).

[0203] In certain embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety comprises a structure according to formula 2:

[0204]

[0205] wherein X 1 、X 2 、X 3 and X 4 is independently selected from -OH, -NH2 and -SH, including their deprotonated variants, depending on chelation to *Cu;

[0206] wherein any methylene group is optionally substituted with oxo, mercapto or hydroxy; and

[0207] wherein represents the point of attachment to the linker moiety (when L is the linker moiety) or to the targeting moiety (when L is a bond).

[0208] In certain embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety comprises a structure according to formula 4':

[0209]

[0210] wherein X 1 、X 2 、X 3 and X 4 is independently selected from -OH, -NH2 and -SH, including their deprotonated variants, depending on chelation to *Cu;

[0211] wherein any methylene group is optionally substituted with oxo, mercapto or hydroxy; and

[0212] wherein represents the point of attachment to the linker moiety (when L is the linker moiety) or to the targeting moiety (when L is a bond).

[0213] In certain embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety comprises a structure according to formula 4i, 4’i or 4ii:

[0214]

[0215] In certain embodiments of the compounds of formulae X, X*, A and A*, the chelating moiety comprises a structure according to formula 4iR or 4iiR.

[0216]

[0217] In various embodiments of the chelating moieties described in this application as formulae 1-4 (including all recited sub-generic formulae), the chelating moiety further comprises one or more groups selected from methylene (-CH2-) and carbonyl (-C(=O)-). In certain embodiments, the chelating moiety further comprises one methylene and one carbonyl, such as -CH2-C(=O)-.

[0218] Embodiments of the chelating moieties described in this application as formulae 1-4 (including all recited sub-generic formulae) are also contemplated, wherein each of the illustrated chelating moieties is further modified to a divalent or multivalent chelating moiety. In certain embodiments, one or more available carboxylic acid carbonyl carbons are the points of attachment to a second targeting moiety and optionally a third targeting moiety (optionally via a linker moiety), thereby replacing a hydroxyl group. In certain embodiments, the methylene carbon is the point of attachment to a second targeting moiety and optionally a third targeting moiety (optionally via a linker moiety).

[0219] 4.2.2. Chelating moiety

[0220] In certain embodiments of the compounds of formulae X* and A*, the compounds of the present disclosure comprise a chelating moiety chelated to a radionuclide (e.g., radioactive copper), i.e., the chelating moiety further comprises a radionuclide metal, or the chelating moiety complexes with a radionuclide metal center. In the embodiments provided below, the bonds represented by lines between the binding moiety and the metal center are for illustrative purposes only, as these interactions are dynamic and depend on the environment.

[0221] In certain embodiments of the compounds of formulae X* and A*, the chelated copper complex (i.e., comprising a chelating moiety and a copper radionuclide) comprises a structure according to formula I:

[0222]

[0223] Wherein:

[0224] R 1 、R 2 and R 3 are each independently C2-6 An alkyl group, optionally substituted with one or more substituents selected from oxo, mercapto, hydroxy, C 1-3 alkoxy, C 1-3 carboxy and C 1-3 alkylthio, including its deprotonated variants, depending on chelation to *Cu;

[0225] wherein R 1 , R 2 and R 3 ≥ one of them contains a point of attachment to a linker moiety (when L is a linker moiety) or to a targeting moiety (when L is a bond).

[0226] In certain embodiments of the compounds of formulae X* and A*, the chelated copper complex comprises a structure according to formula I':

[0227]

[0228] wherein:

[0229] R 1 , R 2 and R 3 are each independently C 2-6 alkyl, optionally substituted with one or more substituents selected from oxo, mercapto, hydroxy, C 1-3 alkoxy, C 1-3 carboxy and C 1-3 alkylthio, including its deprotonated variants, depending on chelation to *Cu;

[0230] where represents a point of attachment to a linker moiety (when L is a linker moiety) or to a targeting moiety (when L is a bond).

[0231] In certain embodiments of the compounds of formulae X* and A*, the chelated copper complex comprises a structure according to formula II:

[0232]

[0233] wherein X 1 , X 2 and X 3 are each independently selected from -OH, -NH2 and -SH, including their deprotonated variants, depending on chelation to *Cu;

[0234] where any methylene group is optionally substituted with oxo, mercapto or hydroxy; and

[0235] where represents a point of attachment to a linker moiety (when L is a linker moiety) or to a targeting moiety (when L is a bond).

[0236] In certain embodiments of the compounds of Formula X* and A*, the chelated copper complex comprises a structure according to Formula II’:

[0237]

[0238] wherein X 1 、X 2 and X 3 are each independently selected from -OH, -NH2, and -SH, including their deprotonated variants, depending on chelation to *Cu;

[0239] wherein any methylene group is optionally substituted with oxo, mercapto, or hydroxy; and

[0240] wherein represents the point of attachment to a linker moiety (when L is a linker moiety) or to a targeting moiety (when L is a bond).

[0241] In certain embodiments of the compounds of Formula X* and A*, the chelated copper complex comprises a structure according to Formula IIi, II’i, IIii, or IIiii:

[0242]

[0243] 4.2.3. Linker Moiety

[0244] In certain embodiments of the compounds of Formula X, X*, A, and A*, the linker moiety (L) is a bond or a monoatomic or polyatomic linkage between the chelating moiety and the targeting moiety. Alternatively, the linker moiety is not particularly limited and can be any linker moiety known in the field of bioconjugation, including linkers known in the construction of antibody-drug conjugates. The linker moiety can be selected based on the ease of synthesis, instability of the linker moiety, solubility of the radiotracer, and other considerations.

[0245] In certain embodiments of the compounds of Formula X, X*, A, and A*, L is divalent, for example when n in Formula X or A is 1, as described herein. In other embodiments, L is polyvalent, thereby linking multiple chelating moieties to the targeting moiety, for example when N is greater than 1, such as an integer from 2 to 10 in Formula X or A, as described herein.

[0246] In certain embodiments of the compounds of Formula X, X*, A, and A*, L comprises one or more chemical entities selected from amino acids, amino acid sequences, 5- to 7-membered carbocyclic or heterocyclic groups, or cyclic heterocycles or acyclic organic molecules, any of which may optionally comprise one or more functional groups selected from ketone, amide, alkyne, azide, amine, and isothiocyanate.

[0247] In certain embodiments of the compounds of Formula X, X*, A and A*, L is a bond such that the targeting moiety is directly attached to the chelating moiety or to multiple chelating moieties.

[0248] In certain embodiments of the compounds of Formula X, X*, A and A*, L is a divalent linker. In certain embodiments, L is a cleavable divalent linker. Cleavable linkers include linkers that are cleaved by intracellular metabolism after internalization, such as by hydrolysis, reduction or enzymatic reaction. In certain embodiments, L is a non-cleavable divalent linker. Non-cleavable linkers include linkers that release the attached payload by lysosomal degradation after internalization.

[0249] In certain embodiments of the compounds of Formula X, X*, A and A*, L is selected from acid-sensitive linkers, hydrolysis-sensitive linkers, enzymatically cleavable linkers, reduction-sensitive linkers, self-immolative linkers and non-cleavable linkers.

[0250] In certain embodiments of the compounds of Formula X, X*, A and A*, L comprises one or more peptides, amino acids, glucuronides, succinimide-sulfides, methylene units, carbonyl units, polyethylene glycol (PEG) units, hydrazones, mal-hexanoyl units, dipeptide units, valine-citrulline units, p-aminobenzyl (PAB) units or combinations thereof.

[0251] In certain embodiments of the compounds of formulae X, X*, A and A*, L comprises one or more amino acids. Suitable amino acids include natural amino acids, unnatural amino acids, standard amino acids, non-standard amino acids, proteinogenic amino acids, non-proteinogenic amino acids, and L- or D-α-amino acids. In certain embodiments, the linker L comprises alanine, valine, glycine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine or citrulline, derivatives thereof, or combinations thereof. In certain embodiments, L comprises a peptide of up to 3 amino acids, up to 5 amino acids, up to 7 amino acids, up to 10 amino acids or up to 15 amino acids. In certain embodiments, L comprises a peptide of 1 to 3 amino acids, 2 to 4 amino acids, 1 to 5 amino acids, 2 to 5 amino acids, 3 to 5 amino acids, 3 - 7 amino acids, 5 - 10 amino acids, 5 - 15 amino acids or 10 - 15 amino acids. In certain embodiments, L is or comprises suberic acid-D-lysine-D-phenylalanine-3-iodo-D-tyrosine (Sub-k-f-(I-y)) = 32-amino-29-benzyl-33-(4-hydroxy-3-iodophenyl)-5,13,20,28,31-pentaoxo-4,6,12,21,27,30-hexaaza-tritriacontane-1,3,7,26-tetracarboxylic acid.

[0252] In certain embodiments of the compounds of formulae X, X*, A and A*, L is a divalent linking group or linking moiety. In certain embodiments, L is or comprises

[0253]

[0254]

[0255] In certain embodiments of the compounds of formulae X, X*, A and A*, L is or comprises In certain embodiments, L is or comprises In certain embodiments, L is or comprises

[0256] In certain embodiments of the compounds of formulae X, X*, A and A*, L is or comprises one or more of a carbonyl, an amine, an amide, an ester, an ether, ethylenediamine among others. In certain embodiments, L is or comprises In certain embodiments, L is or comprises

[0257] The following patent applications disclose suitable linking groups: US Patent Application Publication No. US2011 / 0064657A1 to Pomper et al., regarding "Labeling Inhibitors, Biological Evaluation, and Use as Imaging Agents of Prostate-Specific Membrane Antigen (PSMA)", published on March 17, 2011; and US Patent Application Publication No. US2012 / 0009121A1 to Pomper et al., regarding "PSMA-Targeted Compounds and Their Use", published on January 12, 2012; each of which is incorporated herein by reference in its entirety.

[0258] 4.2.4. Targeting moiety

[0259] There is no particular limitation on the targeting moiety (V) used in the present disclosure, as long as one or more in the targeting moiety can be conjugated to the chelating moiety described in the present application and the targeting moiety interacts with a cell surface target.

[0260] In certain embodiments of the compounds of formula X, X*, A and A*, the targeting moiety is selected from peptides, proteins or small organic molecules that bind to cell surface receptors, such as those expressed by malignant or pre-malignant cells; cells in the tumor microenvironment, such as blood vessels, cancer-associated fibroblasts, stromal matrix and immune cells, inflammatory tissues; and / or tissues at the site of tissue remodeling in myocardial infarction or interstitial lung disease fibrosis.

[0261] In certain embodiments of the compounds of formula X, X*, A and A*, the targeting moiety is a moiety known to target PSMA (prostate-specific membrane antigen), SSTR (somatostatin receptor) and FAP (fibroblast activation protein).

[0262] In certain embodiments of the compounds of formula X, X*, A and A*, the targeting moiety is known to be suitable for conjugation with 68 Ga, 225 Ac or 177 Lu radionuclides. In certain embodiments, the targeting moiety has been used to produce radiotracers for medical imaging or therapy or both.

[0263] In certain embodiments of the compounds of formulae X, X*, A and A*, the targeting moiety is a peptide. The peptide can include natural or unnatural amino acids or combinations thereof. In certain embodiments, the peptide consists of several amino acids linked together by peptide bonds. In other embodiments, the peptide can include up to 50 amino acids. In certain embodiments, the targeting moiety is a peptide of up to 10 amino acids, up to 15 amino acids, up to 20 amino acids, up to 25 amino acids, up to 30 amino acids, up to 35 amino acids, up to 40 amino acids or up to 45 amino acids. In certain embodiments, the targeting moiety is a peptide of 4 - 10 amino acids, 5 - 15 amino acids, 10 - 20 amino acids, 15 - 25 amino acids, 20 - 30 amino acids, 25 - 35 amino acids, 30 - 40 amino acids, 35 - 45 amino acids, 40 - 50 amino acids.

[0264] In certain embodiments of the compounds of formulae X, X*, A and A*, the targeting moiety is specifically recognized by a molecular target (e.g., a peptide or protein) that is expressed (e.g., typically overexpressed) on the surface of cancer cells or in the cancer microenvironment.

[0265] In certain embodiments of the compounds of formulae X, X*, A and A*, the targeting moiety comprises a molecule homologous to a tumor - specific antigen (TSA), which is found to be associated only with cancer cells and not with healthy cells. In certain embodiments, the targeting moiety comprises a molecule homologous to a tumor - associated antigen (TAA), which has an elevated level on tumor cells but is also expressed at a lower level on healthy cells.

[0266] In certain embodiments of the formula X, X*, A, and A* compounds of the targeted chelator constructs and radiotracers of the present disclosure, the targeting moiety includes neurotensin or a functional derivative thereof. In certain embodiments, the targeting moiety includes a molecule that binds to epidermal growth factor receptor 2 (HER2). In certain embodiments, the targeting moiety includes a molecule that binds to prostate-specific antigen (PSA), also known as γ-seminoprotein or kallikrein-3 (KLK3). In certain embodiments, the targeting moiety includes a molecule that binds to tyrosinase-related protein-2 (TRP2), also known as dopachrome tautomerase. In certain embodiments, the targeting moiety includes a molecule that binds to epithelial cell adhesion molecule (EpCAM). In certain embodiments, the targeting moiety includes a molecule that binds to glypican-3 (GPC3). In certain embodiments, the targeting moiety includes a molecule that binds to mesothelin (MSLN), integrin αvβ3, prostate-specific membrane antigen (PSMA). In certain embodiments, the targeting moiety includes a molecule that binds to somatostatin receptor (SSTR). In certain embodiments, the targeting moiety includes a molecule that binds to fibroblast activation protein (FAP). In certain embodiments, the targeting moiety includes a molecule that binds to epidermal growth factor receptor (EGFR).

[0267] 4.2.4.1.1. Target: Neurotensin Receptor

[0268] In certain embodiments of the formula X, X*, A, and A* compounds, the targeting moiety includes neurotensin (NT) or a functional derivative thereof. In certain embodiments, the targeting moiety including neurotensin has previously been demonstrated to have the potential to target tumors such as pancreatic cancer, colorectal cancer, lung cancer, prostate cancer, or breast cancer. In certain embodiments, the targeting moiety includes (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu). In certain embodiments, the targeting moiety includes 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H-pyrazol-3-carbonyl]amino]adamantane-2-carboxylic acid US9868707B2.

[0269] 4.2.4.1.2. Target: Integrin αvβ3

[0270] Integrins are composed of two non-covalently associated transmembrane α and β subunits and are an important molecular family involved in tumor angiogenesis. Integrin αvβ3 is highly expressed in activated endothelial cells, new blood vessels, and some tumor cells, but is absent in quiescent endothelial cells and most normal organ systems, making it a suitable target for anti-angiogenic therapy.

[0271] In embodiments of the compounds of formulae X, X*, A and A*, the targeting moiety comprises a molecule that binds to integrin αvβ3 or αvβ5. In certain embodiments, the targeting moiety comprises LM609 / Avastin, CNTO95, c7E3 Fab, 17E6, Abegrin or a functional derivative of any of them.

[0272] In certain embodiments of the compounds of formulae X, X*, A and A*, the targeting moiety comprises a peptide that binds to αvβ3 integrin. In certain embodiments, the targeting moiety is selected from RGD peptides, SC-68448, SCH221153 and S-247 (shown below). In certain embodiments, the targeting moiety comprises the dimeric RGD peptide E-[c(RGDfK)]2, which is formed by two cyclic pentapeptides c(RGDfK) linked by a glutamate residue. In certain embodiments, the targeting moiety comprises c(RGDfV). In these embodiments, f represents D-phenylalanine. In certain embodiments, the targeting moiety comprises cilengitide, a cyclized RGD-containing pentapeptide, c(RGDf[NMe]V) (shown below). In certain embodiments, the targeting moiety comprises disintegrins, which are a family of low molecular weight (47 - 84 amino acids) cysteine-rich RGD-containing peptides derived from snake venoms.

[0273]

[0274] 4.2.4.1.3. Target: PSMA

[0275] Prostate-specific membrane antigen (PSMA) is a 750-amino acid type II transmembrane glycoprotein that is highly expressed in prostate adenocarcinoma and exhibits only limited expression in benign and extra-prostatic tissues, thus representing an ideal target for prostate cancer diagnosis and management.

[0276] In certain embodiments of the compounds of formulae X, X*, A and A*, the targeting moiety comprises a peptide that binds to ureido prostate-specific membrane antigen (PSMA). In certain embodiments, the targeting moiety comprises an L-lysine-urea-glutamic acid-based PSMA inhibitor, such as Lys-urea-Glu, or the KuE motif.

[0277] In certain embodiments of the compounds of formulae X, X*, A and A*, V is a targeting moiety. In certain embodiments, V is a moiety selected from the group consisting of:

[0278]

[0279]

[0280] In certain embodiments of the compounds of formulae X, X*, A and A*, the targeting moiety comprises In certain embodiments of the compounds of formulae X, X*, A and A*, the targeting moiety comprises In certain embodiments of the compounds of formulae X, X*, A and A*, the targeting moiety comprises In certain embodiments of the compounds of formulae X, X*, A and A*, the targeting moiety comprises

[0281] In certain embodiments, the compound has formula X:

[0282]

[0283] or a pharmaceutically acceptable salt thereof,

[0284] wherein: the chelating moiety is NODAGA;

[0285] L is V is a targeting moiety that binds to PSMA; n is 1; m is 1; p is 1.

[0286] In certain embodiments, the compound of formula X has formula 10:

[0287]

[0288] or a pharmaceutically acceptable salt thereof;

[0289] wherein V comprises a targeting moiety that binds to PSMA.

[0290] In certain embodiments, the compound has formula X*:

[0291]

[0292] or a pharmaceutically acceptable salt thereof,

[0293] wherein: the chelating moiety is NODAGA;

[0294] *Cu is selected from 61 Cu, 62 Cu, 64 Cu and 67Copper radionuclides of Cu;

[0295] L is V is a targeting moiety that binds to PSMA; n is 1; m is 1; p is 1.

[0296] In certain embodiments, the compound comprises a copper atom chelated by the compound of embodiment 1, wherein the compound has the structure of formula 10*:

[0297]

[0298] or a pharmaceutically acceptable salt thereof;

[0299] wherein *Cu is selected from 61 Cu, 62 Cu, 64 Cu and 67 copper radionuclides of Cu.

[0300] 4.2.4.1.4 Target: SSTR

[0301] Neuroendocrine tumors (NETs) most commonly occur in the gastrointestinal tract, pancreas, or lungs. Due to the variable and non-specific initial symptoms, the diagnosis of NETs is usually delayed until advanced stages of the disease. Therefore, surgical resection for cure is not an option for most patients. Somatostatin analogs are the cornerstone of treatment for patients with NETs.

[0302] In certain embodiments of the compounds of formula X, X*, A and A*, the targeting moiety comprises a targeting moiety SST that targets somatostatin receptor 2 (SSTR2). In certain embodiments, the targeting moiety comprises a somatostatin analog (SSA). In certain embodiments, the targeting moiety comprises a cyclic octapeptide analog of somatostatin, such as D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(ol)(Tyr 3 -octreotide) and D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)-Thr(Tyr 3 -octreotide). In certain embodiments, the targeting moiety comprises D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr(ol), i.e., TOC. In certain embodiments, the targeting moiety conforms to the following structure 1, wherein represents the point of attachment to the chelating moiety or linker.

[0303]

[0304] In certain embodiments of the compounds of formula X, X*, A and A*, the targeting moiety comprises p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2, i.e., LM3. LM3 is well known in the art (Fani M et al., J NuClMed 2011;52:1110-8) and can be readily obtained from commercial sources or by conventional synthesis. In certain embodiments, the targeting moiety conforms to Structure 2 below, where represents the point of attachment to the chelating moiety or linker.

[0305]

[0306] In certain embodiments, the compound has the formula X:

[0307]

[0308] or a pharmaceutically acceptable salt thereof,

[0309] wherein: the chelating moiety is NODAGA;

[0310] L is a linker moiety; V is the targeting moiety SST that binds to SSTR; n is 1; m is 1; p is 1.

[0311] In certain embodiments, the compound has the formula X. In certain embodiments, the compound of formula X* has the formula 20:

[0312]

[0313] or a pharmaceutically acceptable salt thereof;

[0314] wherein:

[0315] *Cu is a copper radionuclide selected from 61 Cu, 62 Cu and 67 Cu;

[0316] L is a bond or linker moiety; and

[0317] SST is the targeting moiety that binds to the somatostatin receptor.

[0318] 4.2.4.1.5 Target FAP

[0319] In certain embodiments of the compounds of Formula X, X*, A and A*, the targeting moiety comprises a peptide homologous to fibroblast activation protein (FAP). FAP is overexpressed by cancer-associated fibroblasts in several tumor entities. In certain embodiments of the radiotracers of the present disclosure, the targeting moiety comprises an FAP inhibitor structure, such as Val-boroPro, linagliptin, FAPI-02, or a functional derivative of any of them. Also included are FAP homologs disclosed in Roy et al., Design and validation of fibroblast activation protein alpha targeted imaging and therapeutic agents, Theranostics 2020, 10(13), 5778-5789, which is incorporated herein by reference in its entirety, including but not limited to:

[0320]

[0321] Suitable FAP inhibitors disclosed in the international PCT patent application No. WO2019 / 154886 by Haberkorn et al. published on August 15, 2019, which is incorporated herein by reference in its entirety.

[0322] The present disclosure provides a composition comprising a compound having Formula 30:

[0323]

[0324] Wherein:

[0325] R 1 is R a ;

[0326] R 2 and R 3 each is independently R a or together with the nitrogen atom to which they are attached form a C 2-9 heterocycle;

[0327] R a each occurrence is independently selected from H, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 2-9 heterocyclyl or C 5-9A heteroaryl, optionally substituted with one or more substituents selected from -OH, -OR’, =O, =S, -SH, -SR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, -NR’COR’, halogen, -CN, -CO2H, -CO2R’, -CHO, -COR’, -CONH2, -CONHR’, -CON(R’)2, -NO2, -OP(O)(OH)2, -SO3H, -SO3R’, -SOR’ and -SO2R’, wherein each occurrence of R’ is independently C 1-10 alkyl or C 3-10 cycloalkyl;

[0328] n is an integer from 1 to 20; and

[0329] m is an integer from 1 to 20;

[0330] *Cu is selected from 61 Cu, 62 Cu, 64 Cu and 67 a copper radionuclide of Cu;

[0331] or a pharmaceutically acceptable salt thereof,

[0332] In certain embodiments of the compound of formula 30, R 1 is H. In certain embodiments of the compound of formula 30, R 1 is selected from C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 2-9 heterocyclic group or C 5-9 heteroaryl, optionally substituted with one or more substituents selected from -OH, -OR’, =O, =S, -SH, -SR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, -NR’COR’, halogen, -CN, -CO2H, -CO2R’, -CHO, -COR’, -CONH2, -CONHR’, -CON(R’)2, -NO2, -OP(O)(OH)2, -SO3H, -SO3R’, -SOR’ and -SO2R’, wherein each occurrence of R’ is independently C 1-10 alkyl or C 3-10 cycloalkyl. In certain embodiments of the compound of formula 30, R 1 is selected from H, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10A cycloalkyl group, optionally substituted with one or more substituents selected from -OH, -OR’, =O, =S, -SH, -SR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, -NR’COR’, halogen, -CN, -CO2H, -CO2R’, -CHO, -COR’, -CONH2, -CONHR’, -CON(R’)2, -NO2, -OP(O)(OH)2, -SO3H, -SO3R’, -SOR’ and -SO2R’, where each occurrence of R’ is independently a C 1-10 alkyl or C 3-10 cycloalkyl.

[0333] In certain embodiments of the compound of formula 30, R 1 is selected from H and C 1-10 alkyl. In certain embodiments of the compound of formula 30, R 1 is H. In certain embodiments of the compound of formula 30, R 1 is C 1-10 alkyl. In certain embodiments of the compound of formula 30, R 1 is C1–C6 alkyl. In certain embodiments of the compound of formula 30, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl. In certain embodiments of the compound of formula 30, R 1 is methyl.

[0334] In certain embodiments of the compound of formula 30, R 2 is H. In certain embodiments of the compound of formula 30, R 2 is selected from C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10 cycloalkyl group, optionally substituted with one or more substituents selected from -OH, -OR’, =O, =S, -SH, -SR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, -NR’COR’, halogen, -CN, -CO2H, -CO2R’, -CHO, -COR’, -CONH2, -CONHR’, -CON(R’)2, -NO2, -OP(O)(OH)2, -SO3H, -SO3R’, -SOR’ and -SO2R’, where each occurrence of R’ is independently a C 1-10 alkyl or C 3-10 cycloalkyl.

[0335] In certain embodiments of the compound of formula 30, R 3 is H. In certain embodiments of the compound of formula 30, R 3 is selected from C 1-10Alkyl, C 2-10 Alkenyl, C 3-10 Alkynyl, C 3-10 Cycloalkyl, optionally substituted with one or more substituents selected from -OH, -OR’, =O, =S, -SH, -SR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, -NR’COR’, halogen, -CN, -CO2H, -CO2R’, -CHO, -COR’, -CONH2, -CONHR’, -CON(R’)2, -NO2, -OP(O)(OH)2, -SO3H, -SO3R’, -SOR’ and -SO2R’, where each occurrence of R’ is independently C 1-10 Alkyl or C 3-10 Cycloalkyl.

[0336] In certain embodiments of the compound of formula 30, R 2 and R 3 together with the nitrogen atom to which they are attached form a C 2-9 heterocycle. In certain embodiments of the compound of formula 30, the C 2-9 heterocycle is a 5-, 6- or 7-membered heterocycle. In certain embodiments of the compound of formula 30, the C 2-9 heterocycle is a 5-membered heterocycle selected from pyrrolidine, pyrazolidine and imidazoline. In certain embodiments of the compound of formula 30, the C 2-9 heterocycle is a 6-membered heterocycle selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazane, 1,2,4-triazane and 1,3,5-triazane. In certain embodiments of the compound of formula 30, the C 2-9 heterocycle is piperazine.

[0337] In certain embodiments of the compound of formula 30, n is an integer from 1 to 10. In certain embodiments of the compound of formula 30, n is an integer from 1 to 5. In certain embodiments of the compound of formula 30, n is 1, 2, 3, 4 or 5. In certain embodiments of the compound of formula 30, n is 2.

[0338] In certain embodiments of the compound of formula 30, m is an integer from 1 to 10. In certain embodiments of the compound of formula 30, m is an integer from 1 to 5. In certain embodiments of the compound of formula 30, m is 1, 2, 3, 4 or 5. In certain embodiments of the compound of formula 30, m is 2.

[0339] In certain embodiments of the compound of formula 30, *Cu is selected from 61 Cu, 62 Cu, 64 Cu and 67 Cu copper radionuclides. In certain embodiments of the compound of formula 30, *Cu is61 Cu. In certain embodiments of the compound of Formula 30, *Cu is 62 Cu. In certain embodiments of the compound of Formula 30, *Cu is 64 Cu. In certain embodiments of the compound of Formula 30, *Cu is 62 Cu. In certain embodiments of the compound of Formula 30, *Cu is 67 Cu.

[0340] In certain embodiments of the compound of Formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 is H, R 3 is H, n is an integer from 1 to 20, m is an integer from 1 to 20, and *Cu is selected from 61 Cu and 67 Cu copper radionuclides. In certain embodiments of the compound of Formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 is H, R 3 is H, n is an integer from 1 to 10, m is an integer from 1 to 10, and *Cu is selected from 61 Cu and 67 Cu copper radionuclides. In certain embodiments of the compound of Formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 is H, R 3 is H, n is an integer from 1 to 5, m is an integer from 1 to 5, and *Cu is selected from 61 Cu and 67 Cu copper radionuclides. In certain embodiments of the compound of Formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 is H, R 3 is H, n is 2, m is 2, and *Cu is selected from 61 Cu and 67 Cu copper radionuclides.

[0341] In certain embodiments of the compound of Formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 and R 3 together with the nitrogen atom to which it is attached form a C 2-9 heterocycle, n is an integer from 1 to 20, m is an integer from 1 to 20, and *Cu is selected from 61 Cu and 67 Cu copper radionuclides. In certain embodiments of the compound of Formula 30, R1 Selected from H and C 1-10 alkyl, R 2 and R 3 together with the nitrogen atom to which it is attached form a C 2-9 heterocycle, n is an integer from 1 to 10, m is an integer from 1 to 10, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu. In certain embodiments of the compound of formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 and R 3 together with the nitrogen atom to which it is attached form a C 2-9 heterocycle, n is an integer from 1 to 5, m is an integer from 1 to 5, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu. In certain embodiments of the compound of formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 and R 3 together with the nitrogen atom to which it is attached form a C 2-9 heterocycle, n is 2, m is 2, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu.

[0342] In certain embodiments of the compound of formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 and R 3 together with the nitrogen atoms to which they are attached form a C 2-9 heterocycle, wherein the C 2-9 heterocycle is a 5-, 6- or 7-membered heterocycle, n is an integer from 1 to 20, m is an integer from 1 to 20, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu. In certain embodiments of the compound of formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 and R 3 together with the nitrogen atoms to which they are attached form a C 2-9 heterocycle, wherein the C 2-9 heterocycle is a 5-, 6- or 7-membered heterocycle, n is an integer from 1 to 10, m is an integer from 1 to 10, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu. In certain embodiments of the compound of formula 30, R 1 is selected from H and C 1-10 alkyl, R 2and R 3 together with the nitrogen atom to which they are attached form a C 2-9 heterocycle, wherein the C 2-9 heterocycle is a 5-, 6- or 7-membered heterocycle, n is an integer from 1 to 5, m is an integer from 1 to 5, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu. In certain embodiments of the compound of formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 and R 3 together with the nitrogen atom to which they are attached form a C 2-9 heterocycle, wherein the C 2-9 heterocycle is a 5-, 6- or 7-membered heterocycle, n is 2, m is 2, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu.

[0343] In certain embodiments of the compound of formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 and R 3 together with the nitrogen atom to which it is attached form a C 2-9 heterocycle, wherein the C 2-9 heterocycle is a 6-membered heterocycle, n is an integer from 1 to 20, m is an integer from 1 to 20, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu. In certain embodiments of the compound of formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 and R 3 together with the nitrogen atom to which it is attached form a C 2-9 heterocycle, wherein the C 2-9 heterocycle is a 6-membered heterocycle, n is an integer from 1 to 10, m is an integer from 1 to 10, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu. In certain embodiments of the compound of formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 and R 3 together with the nitrogen atom to which it is attached form a C 2-9 heterocycle, wherein the C 2-9 heterocycle is a 6-membered heterocycle, n is an integer from 1 to 5, m is an integer from 1 to 5, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu. In certain embodiments of the compound of formula 30, R 1 is selected from H and C1-10 alkyl, R 2 and R 3 together with the nitrogen atom to which it is attached form a C 2-9 heterocycle, wherein the C 2-9 heterocycle is a 6-membered heterocycle, n is 2, m is 2, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu.

[0344] In certain embodiments of the compound of formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 and R 3 together with the nitrogen atom to which it is attached form a C 2-9 heterocycle, wherein the C 2-9 heterocycle is piperazine, m is an integer from 1 to 20, n is an integer from 1 to 20, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu. In certain embodiments of the compound of formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 and R 3 together with the nitrogen atom to which it is attached form a C 2-9 heterocycle, wherein the C 2-9 heterocycle is piperazine, m is an integer from 1 to 10, n is an integer from 1 to 10, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu. In certain embodiments of the compound of formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 and R 3 together with the nitrogen atom to which it is attached form a C 2-9 heterocycle, wherein the C 2-9 heterocycle is piperazine, m is an integer from 1 to 5, n is an integer from 1 to 5, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu. In certain embodiments of the compound of formula 30, R 1 is selected from H and C 1-10 alkyl, R 2 and R 3 together with the nitrogen atom to which it is attached form a C 2-9 heterocycle, wherein the C 2-9 heterocycle is piperazine, m is 2, n is 2, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu.

[0345] In certain embodiments of the compound of formula 30, R2 and R 3 together with the nitrogen atom to which they are attached form a piperazine, and m is 2, thereby providing a compound of formula 30a:

[0346]

[0347] or a pharmaceutically acceptable salt thereof, wherein R 1 , n and *Cu are as described above for formula 30.

[0348] In certain embodiments of the compound of formula 30a, R 1 is H. In certain embodiments of the compound of formula 30a, R 1 is selected from C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 2-9 heterocyclic group or C 5-9 heteroaryl, which is optionally substituted with one or more substituents selected from -OH, -OR’, ═O, ═S, -SH, -SR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, -NR’COR’, halogen, -CN, -CO2H, -CO2R’, -CHO, -COR’, -CONH2, -CONHR’, -CON(R’)2, -NO2, -OP(O)(OH)2, -SO3H, -SO3R’, -SOR’ and -SO2R’, wherein R’ is independently C 1-10 alkyl or C 3-10 cycloalkyl each time it appears.

[0349] In certain embodiments of the compound of formula 30a, R 1 is selected from H, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10 cycloalkyl, which is optionally substituted with one or more substituents selected from -OH, -OR’, ═O, ═S, -SH, -SR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, -NR’COR’, halogen, -CN, -CO2H, -CO2R’, -CHO, -COR’, -CONH2, -CONHR’, -CON(R’)2, -NO2, -OP(O)(OH)2, -SO3H, -SO3R’, -SOR’ and -SO2R’, wherein R’ is independently C 1-10 alkyl or C 3-10 cycloalkyl each time it appears.

[0350] In certain embodiments of the compound of Formula 30a, R 1 is selected from H and C 1-10 alkyl. In certain embodiments of the compound of Formula 30a, R 1 is H. In certain embodiments of the compound of Formula 30a, R 1 is C 1-10 alkyl. In certain embodiments of the compound of Formula 30a, R 1 is C1–C6 alkyl. In certain embodiments of the compound of Formula 30a, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. In certain embodiments of the compound of Formula 30a, R 1 is methyl.

[0351] In certain embodiments of the compound of Formula 30a, n is an integer from 1 to 10. In certain embodiments of the compound of Formula 30a, n is an integer from 1 to 5. In certain embodiments of the compound of Formula 30a, n is 1, 2, 3, 4, or 5. In certain embodiments of the compound of Formula 30a, n is 2.

[0352] In certain embodiments of the compound of Formula 30a, *Cu is selected from 61 Cu, 62 Cu, 64 Cu, and 67 Cu copper radionuclides. In certain embodiments of the compound of Formula 30a, *Cu is 61 Cu. In certain embodiments of the compound of Formula 30a, *Cu is 62 Cu. In certain embodiments of the compound of Formula 30a, *Cu is 64 Cu. In certain embodiments of the compound of Formula 30a, *Cu is 62 Cu. In certain embodiments of the compound of Formula 30a, *Cu is 67 Cu.

[0353] In certain embodiments of the compound of Formula 30a, R 1 is selected from H and C 1-10 alkyl, n is an integer from 1 to 20, and *Cu is selected from 61 Cu and 67 Cu copper radionuclides. In certain embodiments of the compound of Formula 30a, R 1 is selected from H and C 1-10 alkyl, n is an integer from 1 to 10, and *Cu is selected from 61 Cu and 67 Cu copper radionuclides. In certain embodiments of the compound of Formula 30a, R 1 is selected from H and C 1-10 alkyl, n is an integer from 1 to 5, and *Cu is selected from61 Cu and 67 copper radionuclides of Cu. In certain embodiments of the compound of Formula 30a, R 1 is selected from H and C 1-10 alkyl, n is 2, and *Cu is selected from 61 Cu and 67 copper radionuclides of Cu.

[0354] In certain embodiments of the compound of Formula 30, R 2 and R 3 are H and m is 2, thereby providing the compound of Formula 30b:

[0355]

[0356] or a pharmaceutically acceptable salt thereof, wherein R 1 , n and *Cu are as described above for Formula 30.

[0357] In certain embodiments of the compound of Formula 30b, R 1 is H. In certain embodiments of the compound of Formula 30b, R 1 is selected from C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 2-9 heterocyclic group or C 5-9 heteroaryl, which is optionally substituted with one or more substituents selected from -OH, -OR’, =O, =S, -SH, -SR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, -NR’COR’, halogen, -CN, -CO2H, -CO2R’, -CHO, -COR’, -CONH2, -CONHR’, -CON(R’)2, -NO2, -OP(O)(OH)2, -SO3H, -SO3R’, -SOR’ and -SO2R’, wherein each occurrence of R’ is independently C 1-10 alkyl or C 3-10 cycloalkyl.

[0358] In certain embodiments of the compound of Formula 30b, R 1 is selected from H, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10A cycloalkyl group, optionally substituted with one or more substituents selected from -OH, -OR’, ═O, ═S, -SH, -SR’, -NH2, -NHR’, -N(R’)2, -NHCOR’, -NR’COR’, halogen, -CN, -CO2H, -CO2R’, -CHO, -COR’, -CONH2, -CONHR’, -CON(R’)2, -NO2, -OP(O)(OH)2, -SO3H, -SO3R’, -SOR’ and -SO2R’, where each occurrence of R’ is independently a C 1-10 alkyl or C 3-10 cycloalkyl.

[0359] In certain embodiments of the compound of formula 30b, R 1 is selected from H and C 1-10 alkyl. In certain embodiments of the compound of formula 30b, R 1 is H. In certain embodiments of the compound of formula 30b, R 1 is C 1-10 alkyl. In certain embodiments of the compound of formula 30b, R 1 is C1–C6 alkyl. In certain embodiments of the compound of formula 30b, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl. In certain embodiments of the compound of formula 30b, R 1 is methyl.

[0360] In certain embodiments of the compound of formula 30b, n is an integer from 1 to 10. In certain embodiments, n is an integer from 1 to 5. In certain embodiments, n is 1, 2, 3, 4 or 5. In certain embodiments, n is 2.

[0361] In certain embodiments of the compound of formula 30b, *Cu is selected from 61 Cu, 62 Cu, 64 Cu and 67 Cu copper radionuclides. In certain embodiments of the compound of formula 30b, *Cu is 61 Cu. In certain embodiments of the compound of formula 30b, *Cu is 62 Cu. In certain embodiments of the compound of formula 30b, *Cu is 64 Cu. In certain embodiments of the compound of formula 30b, *Cu is 62 Cu. In certain embodiments of the compound of formula 30b, *Cu is 67 Cu.

[0362] In certain embodiments of the compound of formula 30b, R 1 is selected from H and C 1-10an alkyl group, n is an integer from 1 to 20, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu. In certain embodiments of the compound of Formula 30b, R 1 is selected from H and C 1-10 an alkyl group, n is an integer from 1 to 10, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu. In certain embodiments of the compound of Formula 30b, R 1 is selected from H and C 1-10 an alkyl group, n is an integer from 1 to 5, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu. In certain embodiments of the compound of Formula 30b, R 1 is selected from H and C 1-10 an alkyl group, n is 2, and *Cu is selected from 61 Cu and 67 a copper radionuclide of Cu.

[0363] In certain embodiments of the compounds of Formulae X, X*, A and A*, the targeting moiety comprises (S)-6-amino-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide). In certain embodiments, the targeting moiety and the linker moiety conform to F1, F2, F3, F4 shown in the following table, where represents the point of attachment to the chelating moiety.

[0364]

[0365]

[0366] 4.2.4.2 Exemplary Compounds

[0367] In certain embodiments of the compounds of Formulae X and A, the compound is one of Structures 1-19 or a pharmaceutically acceptable salt thereof. In certain embodiments, Cu* is in the II oxidation state and is selected from 61 Cu, 62 Cu, 64 Cu and 67 Cu. In certain embodiments, Cu* is 61 Cu. In certain embodiments, Cu* is 67 Cu.

[0368]

[0369]

[0370]

[0371]

[0372]

[0373] In certain embodiments, a composition for medical imaging and / or therapy comprises a targeting chelator construct known in the art to be useful for chelating certain radionuclides (e.g., 64 Cu, 68 Ga or 177 Lu) for medical imaging or therapy.

[0374] Such targeting chelator constructs include the compounds of Structures 8 - 14 shown below.

[0375]

[0376]

[0377]

[0378] In certain embodiments of the compounds of Formula X and A, the compound is selected from Structures 1 - 19 above, or a pharmaceutically acceptable salt thereof, wherein the chelating moiety is replaced by any chelating moiety known to chelate Ga, Lu, or Cu, or a chelating moiety exemplified in the section entitled Chelating Moieties in the present application.

[0379] In certain embodiments of the compounds of Formula X and A, the compound is selected from one of Structures 15 - 24 shown below, or a pharmaceutically acceptable salt thereof.

[0380]

[0381]

[0382]

[0383] In certain embodiments of the compounds of Formula X* and A*, the compound is selected from one of Structures 25 - 34 shown below, or a pharmaceutically acceptable salt thereof.

[0384] In certain embodiments, the diagnostic radiotracer is selected from Compounds 25–34.

[0385]

[0386]

[0387]

[0388] In certain embodiments of the compounds of Formula X* and A*, the compounds are selected from one of the structures 35-43 shown below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compounds are therapeutic radiotracers.

[0389]

[0390]

[0391]

[0392] 4.3. Pharmaceutical Compositions

[0393] One aspect of the present disclosure is to provide high-purity pharmaceutical compositions comprising a compound of Formula X*, a compound of Formula A* or a pharmaceutically acceptable salt thereof. In certain embodiments, these compositions are for medical imaging (diagnostic imaging) and / or therapy. In another aspect, the present invention provides pharmaceutical compositions comprising the compounds of the present disclosure (including compounds of Formula X* and A* and the compounds of the examples) in combination with a pharmaceutically acceptable excipient (e.g., a carrier).

[0394] The pharmaceutical compositions comprise optical isomers, diastereoisomers or pharmaceutically acceptable salts of the inhibitors disclosed in the present application.

[0395] As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient, e.g., an organic or inorganic carrier substance that is pharmaceutically and physiologically acceptable for enteral or parenteral application and that does not react detrimentally with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions such as Ringer's solution, alcohols, oils, gelatin, and carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidone. These formulations may be sterilized and, if desired, may be admixed with auxiliaries such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants, and / or aromatic substances that do not react detrimentally with the compounds of the present invention.

[0396] The compounds of the present invention may be administered to a subject alone, or may be co-administered to a subject. Co-administration means including administering the compounds alone or in combination (more than one) simultaneously or sequentially. If desired, the formulations may also be used in combination with other active substances (e.g., to reduce metabolic degradation).

[0397] In certain embodiments, the compounds described in the present application may be incorporated into pharmaceutical compositions for administration by methods known to those skilled in the art and the methods described in the present application for the provided compounds.

[0398] In certain embodiments, a pharmaceutical composition according to the present disclosure comprises compounds of formula X, X*, A and A*, and the composition further comprises a pharmaceutically acceptable excipient.

[0399] In certain embodiments, a pharmaceutical composition according to the present disclosure is characterized by one or more of the activity and purity characteristics described below.

[0400] 4.3.1. Radioactivity

[0401] The term "radioactivity" (also referred to as activity or total activity) as used in this application refers to the physical quantity defined as the number of radioactive transformations per second occurring in a particular radionuclide. The unit of radioactivity used in this application is the becquerel (symbol Bq), which is defined as equal to the reciprocal of a second (1 / second or s -1 )

[0402] 4.3.2. Molar activity

[0403] The term "molar activity" as used in this application refers to the amount of radioactivity per unit mole of a radiolabeled compound (e.g., the number of nuclear decays per second), expressed in Bq / mol, such as GBq / μmol, for cases where the molecular weight of the labeled material is known.

[0404] In certain embodiments, the composition has a molar activity of from 1 to 280 MBq / nmol, such as from 5 to 265 MBq / nmol, from 10 to 250 MBq / nmol, from 15 to 235 MBq / nmol, from 20 to 220 MBq / nmol, from 25 to 205 MBq / nmol, from 30 to 190 MBq / nmol, from 35 to 175 MBq / nmol, from 40 to 160 MBq / nmol, from 45 to 150 MBq / nmol, from 50 to 135 MBq / nmol, from 55 to 120 MBq / nmol, from 1 to 50 MBq / nmol, from 2 to 48 MBq / nmol, from 4 to 46 MBq / nmol, from 6 to 44 MBq / nmol, from 8 to 42 MBq / nmol, from 10 to 40 MBq / nmol, from 12 to 38 MBq / nmol, from 14 to 36 MBq / nmol, from 16 to 34 MBq / nmol, from 18 to 32 MBq / nmol, from 20 to 30 MBq / nmol or from 22 to 28 MBq / nmol. In certain embodiments, the composition has a molar activity of 24 MBq / nmol ± 3 MBq / nmol.

[0405] In certain embodiments, the composition has a molar activity of ≥35 MBq / nmol, ≥40 MBq / nmol, ≥45 MBq / nmol, ≥50 MBq / nmol, ≥55 MBq / nmol, ≥60 MBq / nmol, ≥65 MBq / nmol, ≥70 MBq / nmol, ≥75 MBq / nmol, ≥80 MBq / nmol, ≥85 MBq / nmol, ≥90 MBq / nmol, ≥95 MBq / nmol, ≥100 MBq / nmol, ≥105 MBq / nmol, ≥110 MBq / nmol, ≥115 MBq / nmol, ≥120 MBq / nmol, ≥125 MBq / nmol, ≥130 MBq / nmol, ≥135 MBq / nmol, ≥140 MBq / nmol, ≥145 MBq / nmol, ≥150 MBq / nmol, ≥155 MBq / nmol, ≥160 MBq / nmol, ≥165 MBq / nmol, ≥170 MBq / nmol, ≥175 MBq / nmol, ≥180 MBq / nmol, ≥185 MBq / nmol, ≥190 MBq / nmol, ≥195 MBq / nmol or ≥200 MBq / nmol.

[0406] In certain embodiments, the composition has a molar activity of 1 to 250 MBq / nmol, such as 1 to 200 MBq / nmol, 1 to 150 MBq / nmol, 1 to 100 MBq / nmol, 1 to 50 MBq / nmol, 50 to 250 MBq / nmol, 50 to 200 MBq / nmol, 50 to 150 MBq / nmol, 50 to 100 MBq / nmol, 100 to 250 MBq / nmol, 100 to 150 MBq / nmol, 150 to 250 MBq / nmol, 150 to 200 MBq / nmol or 200 to 250 MBq / nmol. In certain embodiments, the radiotracer composition is characterized by a molar activity of 1 to 150 MBq / nmol.

[0407] In certain embodiments, the composition has a molar activity of ≥90 MBq / nmol, ≥88 MBq / nmol, ≥86 MBq / nmol, ≥84 MBq / nmol, ≥82 MBq / nmol, ≥80 MBq / nmol, ≥78 MBq / nmol, ≥76 MBq / nmol, ≥74 MBq / nmol, ≥72 MBq / nmol, ≥70 MBq / nmol, ≥68 MBq / nmol, ≥66 MBq / nmol, ≥64 MBq / nmol, ≥62 MBq / nmol, ≥60 MBq / nmol, ≥58 MBq / nmol, ≥56 MBq / nmol, ≥54 MBq / nmol, ≥52 MBq / nmol, ≥50 MBq / nmol, ≥48 MBq / nmol, ≥46 MBq / nmol, ≥44 MBq / nmol, or ≥42 MBq / nmol.

[0408] In certain embodiments of the composition, the composition has a molar activity of ≥3 MBq / nmol, ≥4 MBq / nmol, ≥5 MBq / nmol, ≥6 MBq / nmol, ≥7 MBq / nmol, ≥8 MBq / nmol, ≥9 MBq / nmol, ≥10 MBq / nmol, ≥11 MBq / nmol, ≥12 MBq / nmol, ≥13 MBq / nmol, ≥14 MBq / nmol, ≥15 MBq / nmol, ≥16 MBq / nmol, ≥17 MBq / nmol, ≥18 MBq / nmol, or ≥19 MBq / nmol.

[0409] In certain embodiments of the composition, the composition has a molar activity of ≥ 3 MBq / nmol, ≥ 5 MBq / nmol, ≥ 10 MBq / nmol, ≥ 15 MBq / nmol, ≥ 20 MBq / nmol, ≥ 25 MBq / nmol, ≥ 30 MBq / nmol, ≥ 35 MBq / nmol, ≥ 40 MBq / nmol, ≥ 45 MBq / nmol, ≥ 50 MBq / nmol, ≥ 55 MBq / nmol, ≥ 60 MBq / nmol, ≥ 65 MBq / nmol, ≥ 70 MBq / nmol, ≥ 75 MBq / nmol, ≥ 80 MBq / nmol, ≥ 85 MBq / nmol, ≥ 90 MBq / nmol, ≥ 95 MBq / nmol, ≥ 100 MBq / nmol, ≥ 105 MBq / nmol, ≥ 110 MBq / nmol, ≥ 115 MBq / nmol, ≥ 120 MBq / nmol, ≥ 125 MBq / nmol, 130 MBq / nmol, 135 MBq / nmol, 140 MBq / nmol, 145 MBq / nmol, 150 MBq / nmol, 155 MBq / nmol, ≥ 160 MBq / nmol, ≥ 165 MBq / nmol, ≥ 170 MBq / nmol, ≥ 175 MBq / nmol, ≥ 180 MBq / nmol, ≥ 185 MBq / nmol, ≥ 190 MBq / nmol, ≥ 195 MBq / nmol, ≥ 200 MBq / nmol, ≥ 205 MBq / nmol, ≥ 210 MBq / nmol, ≥ 215 MBq / nmol, 220 ≥ MBq / nmol, ≥ 225 MBq / nmol, ≥ 230 MBq / nmol, ≥ 235 MBq / nmol, ≥ 240 MBq / nmol, ≥ 245 MBq / nmol, ≥ 250 MBq / nmol, ≥ 255 MBq / nmol, ≥ 260 MBq / nmol, ≥ 265 MBq / nmol, ≥ 270 MBq / nmol, ≥ 275 MBq / nmol or ≥ 280 MBq / nmol. In certain embodiments, the composition has a molar activity of ≥ 24 MBq / nmol.

[0410] In certain embodiments, the composition has a molar activity of 1 to 250 MBq / nmol, such as 1 to 200 MBq / nmol, 1 to 150 MBq / nmol, 1 to 100 MBq / nmol, 1 to 50 MBq / nmol, 50 to 250 MBq / nmol, 50 to 200 MBq / nmol, 50 to 150 MBq / nmol, 50 to 100 MBq / nmol, 100 to 250 MBq / nmol, 100 to 150 MBq / nmol, 150 to 250 MBq / nmol, 150 to 200 MBq / nmol or 200 to 250 MBq / nmol.

[0411] 4.3.3. Radioactive concentration

[0412] The term "radioactive concentration" as used in this application refers to the total amount of radioactivity per unit volume. In certain embodiments, the radioactive concentration is expressed in Bq / L or an order of magnitude thereof (such as MBq / mL).

[0413] In certain embodiments, the provided composition is characterized by a radioactivity concentration ≥ 8 MBq / mL. In certain embodiments, the composition provided in the present application is characterized by a radioactivity concentration of 8 to 10 MBq / mL, 10 to 20 MBq / mL, 20 to 30 MBq / mL, 30 to 40 MBq / mL, 40 to 50 MBq / mL, 50 to 60 MBq / mL, 60 to 70 MBq / mL, 70 to 80 MBq / mL, 80 to 90 MBq / mL, 90 to 100 MBq / mL, 100 to 110 MBq / mL, 110 to 120 MBq / mL, 120 to 130 MBq / mL, 130 to 140 MBq / mL, 140 to 150 MBq / mL, 150 to 160 MBq / mL, 160 to 170 MBq / mL, 170 to 180 MBq / mL, 180 to 190 MBq / mL, 190 to 200 MBq / mL, 200 to 210 MBq / mL, 210 to 220 MBq / mL, 220 to 230 MBq / mL, 230 to 240 MBq / mL, 240 to 250 MBq / mL, 250 to 260 MBq / mL, 260 to 270 MBq / mL, 270 to 280 MBq / mL, 280 to 290 MBq / mL, 290 to 300 MBq / mL, 300 to 310 MBq / mL, 310 to 320 MBq / mL, 320 to 330 MBq / mL, 330 to 340 MBq / mL, 340 to 350 MBq / mL,350 to 360 MBq / mL, 360 to 370 MBq / mL, 370 to 380 MBq / mL, 380 to 390 MBq / mL, 390 to 400 MBq / mL, 400 to 410 MBq / mL, 410 to 420 MBq / mL, 420 to 430 MBq / mL, 430 to 440 MBq / mL, 440 to 450 MBq / mL, 450 to 460 MBq / mL, 460 to 470 MBq / mL, 470 to 480 MBq / mL, 480 to 490 MBq / mL, 490 to 500 MBq / mL, 500 to 510 MBq / mL, 510 to 520 MBq / mL, 520 to 530 MBq / mL, 530 to 540 MBq / mL, 540 to 550 MBq / mL, 550 to 560 MBq / mL, 560 to 570 MBq / mL, 570 to 580 MBq / mL, 580 to 590 MBq / mL, 590 to 600 MBq / mL, 600 to 610 MBq / mL, 610 to 620 MBq / mL, 620 to 630 MBq / mL, 630 to 640 MBq / mL, 640 to 650 MBq / mL, 650 to 660 MBq / mL, 660 to 670 MBq / mL, 670 to 680 MBq / mL, 680 to 690 MBq / mL, 690 to 700 MBq / mL, 700 to 710 MBq / mL, 710 to 720 MBq / mL, 720 to 730 MBq / mL, 730 to 740 MBq / mL, 740 to 750 MBq / mL, 750 to 760 MBq / mL, 760 to 770 MBq / mL, 770 to 780 MBq / mL, 780 to 790 MBq / mL, 790 to 800 MBq / mL, 800 to 810 MBq / mL, 810 to 820 MBq / mL, 820 to 830 MBq / mL, 830 to 840 MBq / mL, 840 to 850 MBq / mL, 850 to 860 MBq / mL, 860 to 870 MBq / mL, 870 to 880 MBq / mL, 880 to 890 MBq / mL, 890 to 900 MBq / mL, 900 to 910 MBq / mL, 910 to 920 MBq / mL, 920 to 930 MBq / mL, 930 to 940 MBq / mL, 940 to 950 MBq / mL, 950 to 960 MBq / mL, 960 to 970 MBq / mL, 970 to 980 MBq / mL, 980 to 990 MBq / mL or 990 to 1000 MBq / mL.,

[0414] In certain embodiments, the provided composition is characterized by a radioactivity concentration ≥ 8 MBq / mL. In certain embodiments, the provided composition is characterized by a radioactivity concentration of 5 to 500 MBq / mL, 20 to 480 MBq / mL, 40 to 460 MBq / mL, 60 to 440 MBq / mL, 80 to 420 MBq / mL, 100 to 400 MBq / mL, 120 to 380 MBq / mL, 140 to 360 MBq / mL, 160 to 340 MBq / mL, 180 to 320 MBq / mL, or 200 to 300 MBq / mL.

[0415] In certain embodiments, the provided composition is characterized by a radioactivity concentration ≥ 3 MBq / mL, ≥ 4 MBq / mL, ≥ 5 MBq / mL, ≥ 6 MBq / mL, ≥ 7 MBq / mL, ≥ 8 MBq / mL, ≥ 9 MBq / mL, ≥ 10 MBq / mL, ≥ 12 MBq / mL, ≥ 15 MBq / mL, ≥ 20 MBq / mL, ≥ 25 MBq / mL, ≥ 30 MBq / mL, ≥ 35 MBq / mL, ≥ 40 MBq / mL, ≥ 45 MBq / mL, ≥ 50 MBq / mL, ≥ 55 MBq / mL, ≥ 60 MBq / mL, ≥ 65 MBq / mL, ≥ 70 MBq / mL, ≥ 75 MBq / mL, ≥ 80 MBq / mL, ≥ 85 MBq / mL, ≥ 90 MBq / mL, ≥ 95 MBq / mL, ≥ 100 MBq / mL, ≥ 105 MBq / mL, ≥ 110 MBq / mL, ≥ 115 MBq / mL, ≥ 120 MBq / mL, ≥ 125 MBq / mL, 130 MBq / mL, 135 MBq / mL, 140 MBq / mL, 145 MBq / mL, 150 MBq / mL, 155 MBq / mL, ≥ 160 MBq / mL, ≥ 165 MBq / mL, ≥ 170 MBq / mL, ≥ 175 MBq / mL, ≥ 180 MBq / mL, ≥ 185 MBq / mL, ≥ 190 MBq / mL, ≥ 195 MBq / mL, ≥ 200 MBq / mL, ≥ 205 MBq / mL, ≥ 210 MBq / mL, ≥ 215 MBq / mL, 220 ≥ MBq / mL, ≥ 225 MBq / mL, ≥ 230 MBq / mL, ≥ 235 MBq / mL, ≥ 240 MBq / mL, ≥ 245 MBq / mL, ≥ 250 MBq / mL, ≥ 255 MBq / mL, ≥ 260 MBq / mL, ≥ 265 MBq / mL, ≥ 270 MBq / mL, ≥ 275 MBq / mL, or ≥ 280 MBq / mL.

[0416] In certain embodiments, the radioactivity concentration of the resulting pharmaceutical composition may be diluted (e.g., diluted 3 to 10 times), provided that the radioactivity concentration ≥ 8 MBq / mL. In certain embodiments, the radioactivity concentration of the composition is 8 to 20 MBq / mL, 9 to 19 MBq / mL, 10 to 18 MBq / mL, 11 to 19 MBq / mL, 12 to 18 MBq / mL, 13 to 15 MBq / mL, 14 to 15 MBq / mL, 8 to 14 MBq / mL, 8 to 13 MBq / mL, 8 to 12 MBq / mL, 8 to 11 MBq / mL, 8 to 10 MBq / mL, 8 to 9 MBq / mL, 9 to 14 MBq / mL, 10 to 13 MBq / mL, or 11 to 12 MBq / mL.

[0417] In certain embodiments, the provided pharmaceutical formulation composition is characterized by a radioactivity concentration of 0.3 to 0.75 GBq / mL.

[0418] 4.3.4. Radiochemical Purity

[0419] As understood in the present application, "radiochemical purity" is the ratio (expressed as a percentage) of the radioactivity of the desired radionuclide in a radiopharmaceutical composition (e.g., the desired radionuclide chelated in the radiotracer described in the present application) to the total radioactivity of the composition containing the radiopharmaceutical. It is important to know that most of the radioisotopes are attached to the tracer construct rather than being free or attached to another chemical entity, as these forms may have different biodistributions. The radiochemical purity (RCP) measurement determines the content of impurities with the same radionuclide label but different chemical forms used in the preparation of the radiopharmaceutical. For most radiopharmaceuticals, the lower limit of radiochemical purity is 95%, i.e., at least 95% of the radioisotopes must be attached to the ligand. The radiochemical purity determination can be carried out by various chromatographic methods.

[0420] The radiochemical purity is determined according to methods well known to those skilled in the art, such as radioactive HPLC, iTLC, and / or γ spectrometry. As understood in the art, the determination of radiochemical purity is not strictly quantitative, but is calculated as the ratio between the peak area of the desired radiopharmaceutical and the total area of all detected peaks (attenuation corrected) in the radiochromatogram. The instrument for determining radiochemical purity using HPLC (radioactive HPLC) is a radioactive detector (radioactive detector) with an on-line detector connected in series with a UV or other physicochemical detector. The radioactive detector can be a Geiger-Mueller probe, a scintillation detector, or a PIN diode. Compared with radioactive HPLC, it has the great advantage that all the applied radioactivity is detected and there is no concern about recovery.

[0421] In certain embodiments, the composition is characterized by a radiochemical purity of ≥90%. In certain embodiments, the composition is characterized by a radiochemical purity of ≥91%, ≥92%, ≥93%, ≥94%, 95%, ≥96%, ≥97%, ≥98%, or ≥99%. In certain embodiments, the composition is characterized by a radiochemical purity of ≥90%. In certain embodiments, the composition is characterized by a radiochemical purity of ≥95%. In certain embodiments, the composition is characterized by a radiochemical purity of ≥96%. In certain embodiments, the composition is characterized by a radiochemical purity of ≥98%.

[0422] In certain embodiments, the provided composition is characterized by a radiochemical purity of ≥94.0%, ≥94.5%, ≥95.0%, ≥95.5%, ≥96.0%, ≥96.5%, ≥97.0%, ≥97.5%, ≥98.0%, ≥98.5%, ≥99.0%, or ≥99.5%.

[0423] In certain embodiments, the provided composition is characterized by a radiochemical purity of ≥95.2%, ≥95.4%, ≥95.6%, ≥95.8%, ≥96%, ≥96.2%, ≥96.4%, ≥96.6%, ≥96.8%, ≥97%, ≥97.2%, ≥97.4%, ≥97.6%, ≥97.8%, ≥98%, ≥98.2%, ≥98.4%, ≥98.6%, ≥98.8%, ≥99%, ≥99.2%, ≥99.4%, ≥99.6%, or ≥99.8%.

[0424] 4.3.5. Radionuclide Purity

[0425] The term "radionuclide purity" as used in this application refers to the ratio (expressed as a percentage) of the radioactivity of the desired radionuclide to the total radioactivity of the sample (e.g., the starting material used to prepare the radiolabeled drug). As reported in this application, unless otherwise stated, the radionuclide purity is determined by high-resolution gamma spectrometry (e.g., a high-purity germanium (HPGe) detector) on the sample after expiration (e.g., >8 hours or >3 weeks), then extrapolated (e.g., using the TENDLE-2019 database according to procedures well known in the art), and reported in this application as the value at the end of radionuclide synthesis (EoB + 2 hours).

[0426] In certain embodiments, the composition is characterized by a radionuclide purity of ≥85% of the compound at the end of synthesis, such as ≥86%, ≥87%, ≥88%, ≥89%, ≥90%, ≥91%, ≥92%, ≥93%, ≥94%, ≥95%, ≥96%, ≥97%, ≥98%, or ≥99%.

[0427] In certain embodiments, the composition is characterized in that the radionuclide purity of the compound at the end of synthesis is ≥90.5%, such as ≥91%, ≥91.5%, ≥92%, ≥92.5%, ≥93%, ≥93.5%, ≥94%, ≥94.5%, ≥95%, ≥95.5%, ≥96%, ≥96.5%, ≥97%, ≥97.5%, ≥98%, ≥98.5%, ≥99% or ≥99.5%.

[0428] In certain embodiments, the composition is characterized in that the radionuclide purity is ≥95.1%, such as ≥95.2%, ≥95.3%, ≥95.4%, ≥95.5%, ≥95.6%, ≥95.7%, ≥95.8%, ≥95.9%, ≥96%, ≥96.1%, ≥96.2%, ≥96.3%, ≥96.4%, ≥96.5%, ≥96.6%, ≥96.7%, ≥96.8%, ≥96.9%, ≥97%, ≥97.1%, ≥97.2%, ≥97.3%, ≥97.4%, ≥97.5%, ≥97.6%, ≥97.7%, ≥97.8%, 97.9%, ≥98%, ≥98.1%, ≥98.2%, ≥98.3%, ≥98.4%, ≥98.5%, ≥98.6%, ≥98.7%, ≥98.8%, ≥98.9%, ≥99%, ≥99.1%, ≥99.2%, ≥99.3%, ≥99.4%, ≥99.5%, ≥99.6%, ≥99.7%, ≥99.8% or ≥99.9%.

[0429] In certain embodiments, the composition is characterized in that the radionuclide purity is ≥97% (at the end of synthesis). In certain embodiments, the composition is characterized in that the radionuclide purity is ≥93%, ≥94%, ≥95%, ≥96%, ≥98% or ≥99% (at the end of synthesis).

[0430] 4.3.6. Formulations

[0431] The compounds of the present invention can be prepared and administered in a wide variety of oral dosage forms, parenteral dosage forms and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g., intravenous injection, intramuscular injection, intradermal injection, subcutaneous injection, duodenal injection or intraperitoneal injection). In certain embodiments, the compounds of the present disclosure are administered orally. In addition, the compounds described in the present application can be administered by inhalation, such as intranasal inhalation. In addition, the compounds of the present invention can be administered transdermally. It is also contemplated that a variety of administration routes (e.g., intramuscular, oral, transdermal) can be used to administer the compounds of the present invention. Accordingly, the present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the present invention.

[0432] For preparing the pharmaceutical compositions of the compounds of the present invention, pharmaceutically acceptable carriers can be solid or liquid. Solid formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances, which can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrants, or encapsulating materials.

[0433] In powders, the carrier is a finely divided solid which is mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compressed into the required shape and size.

[0434] 4.3.7. Effective Dose

[0435] The pharmaceutical compositions provided by the present disclosure include compositions containing a therapeutically effective amount (i.e., an amount effective to achieve its intended purpose) of an active ingredient. The actual amount effective for a particular application will depend especially on the disorder being treated or the image being generated. For example, when administered in a method of treating cancer, such compositions will contain an amount of the active ingredient effective to achieve the desired result (e.g., imaging cancerous tissue and / or reducing the amount of cancerous tissue in a subject).

[0436] The dosage and frequency (single dose or multiple doses) of the compound administered can vary according to a variety of factors, including the route of administration; the body size, age, sex, health status, weight, body mass index, and diet of the recipient; the nature and extent of the symptoms of the disease being treated (e.g., disease-responsive treatment; and any complications of the disease or treatment regimen). Other treatment regimens or agents can be used in combination with the methods and compounds of the present invention.

[0437] For any provided compound or test reagent, a diagnostically effective amount or a therapeutically effective amount can be determined first by cell culture assays and / or animal testing. The target concentration will be the concentration of the active compound capable of diagnosing, monitoring, and / or treating cancer in a patient or subject.

[0438] The therapeutically effective amount for human use can be determined according to animal model formulations. For example, human doses can be formulated to achieve the concentration found to be effective in animals. The human dose can be adjusted by monitoring cancer growth, proliferation, and / or metastasis and adjusting the dose up or down, as described above.

[0439] The dose can vary, depending on the requirements of the patient and the compound used. In the context of the present invention, the dose administered to a patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by dose escalation trials during the clinical trial phase.

[0440] In one aspect, when compared to a reference compound, the compounds provided in the present application exhibit one or more improved pharmacokinetic (PK) properties (e.g., Cmax, tmax, Cmin, t1 / 2, AUC, CL, bioavailability, etc.). In certain embodiments, the reference compound is a PSMA, SSTR2, or FAP PET radiotracer.

[0441] In certain embodiments, the compounds of the present disclosure or pharmaceutical compositions comprising the compound are provided in unit dosage. In certain embodiments, the compounds of the present disclosure or radiopharmaceutical compositions comprising the compound are provided in unit dosage (e.g., molar activity).

[0442] In certain embodiments, the pharmaceutical compositions of the present disclosure are administered together with a loop diuretic (e.g., furosemide). In certain embodiments, the pharmaceutical compositions of the present disclosure are administered to a subject who is also administered any one of spironolactone, bumetanide, ethacrynic acid, torasemide, hydrochlorothiazide, furosemide, or metolazone.

[0443] In certain embodiments, the pharmaceutical compositions of the present disclosure are administered to a subject who is also administered any one of the drugs selected from lysine, gelofusine, docetaxel, everolimus, abiraterone acetate, enzalutamide, olaparib, temozolomide, acetazolamide, or succinylacetone.

[0444] 4.4. Methods of Use

[0445] The present disclosure provides compounds and pharmaceutical compositions comprising the compound for medical use, i.e., for treatment, imaging, diagnosis, companion diagnosis, etc. The present disclosure also provides the use of any of the compounds described in the present application for targeted radiotherapy, which will be beneficial for the diagnosis and / or treatment of cancer.

[0446] In certain embodiments, the compounds or pharmaceutical compositions of the present disclosure are administered to the subject once a day, twice a day, daily, or every other day. In certain embodiments, the compounds or pharmaceutical compositions of the present disclosure are administered to the subject twice a week, once a week, every ten days, every two weeks, every three weeks, every four weeks, once a month, every six weeks, every eight weeks, every three months, every four months, every six months, every eight months, every nine months, or annually. The dose and frequency (single dose or multiple doses) of the compound or pharmaceutical composition administered can vary depending on a variety of factors, including the route of administration; the size, age, gender, health status, weight, body mass index, and diet of the recipient; the nature and severity of the symptoms of the disease being treated (e.g., disease-responsive therapy) and any complications of any disease or treatment regimen. Other treatment regimens or agents can be used in combination with the methods and compounds of the present invention.

[0447] For any provided compound or pharmaceutical composition, an effective amount (e.g., a diagnostically effective amount or a therapeutically effective amount) can be determined initially by cell culture assays and / or animal testing. The target concentration will be the concentration of the active compound that is capable of diagnosing, monitoring, and / or treating cancer in a patient or subject.

[0448] The therapeutic effect of a compound can be determined using animal models. During clinical trials, the human dosage can be adjusted by monitoring safety and efficacy via dose escalation studies.

[0449] The dosage can vary depending on the needs of the patient and the compound or pharmaceutical composition used. In the context of the present invention, the dosage administered to a patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dosage will also be determined by the presence, nature, and extent of any adverse side effects.

[0450] Compared to reference compounds, the compounds provided in the present application exhibit one or more improved pharmacokinetic (PK) properties (e.g., Cmax, tmax, Cmin, t1 / 2, AUC, CL, bioavailability, etc.).

[0451] In some embodiments, the compounds of the present disclosure or pharmaceutical compositions comprising the compound are provided in unit dosage.

[0452] In another aspect, the present disclosure provides novel radiotracers and / or novel radiotracer compositions as provided above for use in methods of imaging, diagnosing, and / or staging cancer. In certain embodiments, the cancer is selected from breast cancer (e.g., triple-negative breast cancer), pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer), head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumors, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

[0453] In certain embodiments, the cancer is prostate cancer. Prostate cancer is not the only cancer that expresses PSMA. Non-prostate cancers known to demonstrate PSMA expression include breast cancer, lung cancer, colorectal cancer, and renal cell carcinoma. Accordingly, any compound having a PSMA binding moiety as described herein can be used for the diagnosis, imaging, or treatment of cancers having PSMA expression. Preferred indications are the detection or staging of cancer, such as but not limited to high-grade glioma, lung cancer, particularly prostate cancer and metastatic prostate cancer, detection of metastatic disease in patients with intermediate- to high-risk primary prostate cancer, and detection of the site of metastasis, even in the case of low serum PSA values in patients with biochemically recurrent prostate cancer. Another preferred indication is the imaging and visualization of angiogenesis.

[0454] In terms of medical indications for undergoing treatment, particularly radiotherapy, cancer is a preferred indication. Prostate cancer is a particularly preferred indication.

[0455] In certain embodiments, the method comprises administering to a subject in need thereof (e.g., a subject such as a human patient) any compound or a pharmaceutically acceptable salt thereof as described herein. In certain embodiments, the method comprises administering to a subject in need thereof a pharmaceutically acceptable salt or composition of a compound of formula X*, A*, 10*, a compound of Structure 24-36, or any one of these compounds provided herein. In certain embodiments, the method comprises administering to a subject in need thereof a pharmaceutical composition comprising a provided compound of formula X* or A*, a compound of Structure 24-36, or a pharmaceutically acceptable salt.

[0456] 4.4.1.1 Imaging and Diagnosis

[0457] In one aspect of the present disclosure, there is provided a method of generating an image of a subject (e.g., a region or portion of the body), the method comprising administering to the subject a compound comprising a radionuclide as described herein. In certain embodiments, the radionuclide is selected from 60 Cu, 61 Cu, 62 Cu, 64 Cu, and 67 Cu. In certain embodiments, the radionuclide is 61 Cu. In certain embodiments, the radionuclide is 67 Cu.

[0458] In certain embodiments, provided is a method of generating one or more images of a subject (e.g., a region or portion of the subject's body), the method comprising administering to the subject an effective amount of a compound comprising a radionuclide described herein or a pharmaceutical composition comprising the compound, and generating one or more images of at least a portion of the subject's body. In certain embodiments, two or more images of the subject are generated, e.g., three or more images, four or more images, or five or more images. In certain embodiments, a diagnostically effective amount of a compound comprising a radionuclide or a pharmaceutical composition comprising the compound is administered to the subject, i.e., an amount sufficient to (visually or computationally) identify the localization of the radionuclide within a region or portion of the subject's body. In some embodiments, the radionuclide is a metallic radionuclide. In certain embodiments, the radionuclide is selected from 60 Cu, 61 Cu, 62 Cu, 64 Cu, and 67 Cu. In some embodiments, the radionuclide is 61 Cu.

[0459] In certain embodiments, one or more images are generated using positron emission tomography (PET). In certain embodiments, one or more images are generated using PET computed tomography (PET-CT). In certain embodiments, one or more images are generated using single photon emission computed tomography (SPECT).

[0460] In certain embodiments, the image is generated using PET or PET-CT, wherein the radionuclide is 61 Cu. In certain embodiments, the image is generated using SPECT, wherein the radionuclide is 61 Cu or 67 Cu.

[0461] In certain embodiments, after one or more images are generated, the method further comprises determining the presence or absence of a disease in the subject based on the presence or absence of radionuclide localization in one or more images of the subject's body.

[0462] In another aspect of the present disclosure, a method of monitoring the effect of cancer treatment on a subject with cancer is provided. The method includes administering to the subject a compound comprising a radionuclide as described in the present application, detecting the localization of the compound in the subject using, for example, PET or SPECT, and determining the efficacy of the cancer treatment. In certain embodiments, the compound is administered to the subject and the localization is observed at multiple time points, i.e., at an earlier time point (e.g., before the start of cancer treatment (t = 0)) and at a later time point, e.g., 1 month after the start of treatment, 2 months after the start of treatment, 3 months after the start of treatment, 4 months after the start of treatment, 5 months after the start of treatment, or 6 months after the start of treatment or longer. If less localization is observed at the later time point compared to the earlier time point, it is determined that the cancer treatment is beneficial (i.e., has a positive effect). If more localization is observed at the later time point compared to the earlier time point, it is determined that the cancer treatment is not beneficial (i.e., has a negative impact). If there is no difference in localization at the later time point compared to the earlier time point, it is determined that the cancer treatment is ineffective.

[0463] In certain embodiments, the diseases detected include cancer, such as tumors expressing somatostatin receptors such as neuroendocrine tumors, prostate cancer, malignant meningioma, epithelial cancers overexpressing FAP including non-small cell lung cancer, triple-negative breast cancer, colorectal cancer, gastric cancer, ovarian cancer, and pancreatic cancer; myocardial infarction and interstitial lung disease. In certain embodiments, the cancer is selected from breast cancer (e.g., triple-negative breast cancer), pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer), head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic cancer, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

[0464] In another aspect of the present disclosure, a method for monitoring the effect of cancer treatment on a subject with cancer is provided. The method includes administering to the subject an effective amount of a compound comprising a radionuclide described in the present application or a pharmaceutical composition comprising the compound; detecting the localization of the radionuclide in the subject using, for example, PET, PET-CT or SPECT; and determining the effect of the cancer treatment. In certain embodiments, a compound comprising a radionuclide or a pharmaceutical composition comprising a radionuclide is administered to the subject, and localization is observed at multiple time points, i.e., at an earlier time point (e.g., before the start of cancer treatment (t = 0)) and at a later time point, e.g., 2 weeks after the start of treatment, 3 weeks after the start of treatment, 1 month after the start of treatment, 2 months after the start of treatment, 3 months after the start of treatment, 4 months after the start of treatment, 5 months after the start of treatment or 6 months after the start of treatment or longer. In certain but not all embodiments, if less localization is observed at the later time point compared to the earlier time point, it is determined that the cancer treatment is beneficial (i.e., has a positive effect). In certain but not all embodiments, if more localization is observed at the later time point compared to the earlier time point, it is determined that the cancer treatment is not beneficial (i.e., has a negative effect). In certain but not all embodiments, if there is no difference in localization at the later time point compared to the earlier time point, it is determined that the cancer treatment has no effect.

[0465] 4.4.1.2 Treatment

[0466] In one aspect, the present disclosure provides a method for treating a disease in a patient suffering from the disease, the method comprising administering to the patient an effective amount of the compound or pharmaceutical composition described in the present application.

[0467] In certain embodiments, a method for providing radionuclide therapy to a cancer patient in need is provided, the method comprising administering to the cancer patient an effective amount of a high-purity radiotracer composition as described in the present application, wherein *Cu is 64 Cu or 67 Cu.

[0468] In certain embodiments, the administered compound has formula X, wherein the compound comprises a selection from 64 Cu and 67Radioisotopes of Cu. Such embodiments can be used to treat cancers such as breast cancer (e.g., triple-negative breast cancer), pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer), head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumors, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

[0469] In a further embodiment of the above method, the cancer is selected from tumors expressing somatostatin receptors such as neuroendocrine tumors, prostate cancer, malignant meningioma, epithelial cancers overexpressing FAP including non-small cell lung cancer, triple-negative breast cancer, head and neck cancer, colorectal cancer, gastric cancer, ovarian cancer, and pancreatic cancer.

[0470] 4.4.1.3 Theranostics

[0471] In one aspect of the present disclosure, a theranostic method includes using a pair of *Cu radiotracers provided in this application (“theranostic pair”) for imaging / diagnosis and treatment of a disease in the same patient, wherein the theranostic pair of radiotracers differ only in terms of the radioisotope, i.e., they are different radioactive isotopes. In certain embodiments, the theranostic pair includes a γ or positron-emitting radioisotope in the radiotracer for imaging / diagnosis (e.g., using PET, PET-CT, or SPECT) and a β-emitting radioisotope in the radiotracer for treatment.

[0472] In certain embodiments, the theranostic pair includes 61 Cu (for imaging / diagnosis) and 67 Cu (for treatment). In certain embodiments, this is referred to as 61 / 67 Cu theranostic pair.

[0473] Certain embodiments of the theranostic method include administering a diagnostic form of the radiotracer (e.g., for PET where *Cu is 61 Cu, or for SPECT where *Cu is 67 Cu), such that before conversion to the radiolabeled therapeutic counterpart, e.g., where *Cu is 64 Cu or 67 Cu, the expression of the therapeutic target can be visualized in vivo using an accompanying imaging method.

[0474] In certain embodiments, the theranostic method includes:

[0475] (a) Administering to the subject an effective amount of a compound comprising a 61 Cu radionuclide or a pharmaceutical composition comprising the compound;

[0476] (b) Generating one or more images of the subject (e.g., a region or portion of the subject's body); and

[0477] (c) Administering to the subject an effective amount of a compound comprising a 67 Cu radionuclide or a pharmaceutical composition comprising the compound, wherein the compounds of steps (a) and (c) differ only in their radioisotope identity.

[0478] In certain embodiments, the amount of the compound comprising a 61 Cu radionuclide or the pharmaceutical composition comprising the compound administered in step (a) is effective to produce one or more images of the subject (i.e., a "detectable effective amount"). In certain embodiments, the amount of the compound comprising a 61 Cu radionuclide or the pharmaceutical composition comprising the compound administered in step (a) is effective to diagnose the presence or absence of a disease (i.e., a "diagnostic effective amount").

[0479] In certain embodiments, the method further comprises determining, from one or more images of the subject, whether the subject has a disease based on the presence or absence of the localization of a 61 Cu radionuclide in the subject. If the subject is not determined to have a disease, step (c) of the method is not performed.

[0480] In certain embodiments, the method further comprises calculating an effective therapeutic amount of the compound comprising a 67 Cu radionuclide administered to the subject in step (c). In certain embodiments, the method further comprises calculating an effective therapeutic dose of the compound comprising a 67 Cu radionuclide administered to the subject in step (c).

[0481] In certain embodiments, the amount of the compound comprising a 67 Cu radionuclide or the pharmaceutical composition comprising the compound administered in step (c) is therapeutically effective to treat the disease of the subject (i.e., a "therapeutic effective amount").

[0482] In certain embodiments, the theranostic method comprises:

[0483] (a) Generating one or more images of the subject (e.g., a region or portion of the subject's body), including administering to the subject an effective amount of a composition comprising that described in the present application61 Compounds of Cu radionuclides or pharmaceutical compositions comprising such compounds;

[0484] (b) Based on the presence or absence of the localization of the 61 Cu radionuclide in the subject, determining whether a disease exists in the subject through one or more images of the subject; and

[0485] (c) When it is determined that the subject has a disease, administering to the subject an effective amount of the compound or pharmaceutical composition comprising the 67 Cu radionuclide provided in the present application, wherein the compounds in steps (a) and (c) differ only in the radionuclide identity.

[0486] 4.5. Method for making a composition

[0487] In certain embodiments, the methods for preparing the compounds and compositions according to Formulas X* and A* provided in the present application include the following steps

[0488] (a) Combining a high-purity radioactive copper solution with:

[0489] (b) The compounds provided in the present application, such as compounds according to Formula X, such as Formula A compounds, wherein the compounds comprise *Cu.

[0490] In certain embodiments, the combining occurs at an elevated temperature (80 - 95 °C) within a reaction time of 15 minutes. In certain embodiments, the combining occurs at room temperature within a reaction time of 15 minutes. In certain embodiments, the combining occurs at room temperature within a reaction time of 2 - 5 minutes. In certain embodiments, the combining occurs in a suitable buffer solution (e.g., ammonium acetate buffer, 0.5 M, pH = 8).

[0491] In certain embodiments, no further purification step is required to remove the uncomplexed 61 Cu reaction mixture, allowing the direct use of the formed compound.

[0492] 4.5.1. Radiolabeling yield (radiochemical yield)

[0493] The radiochemical yield is the amount of radioactivity in the product, expressed as a percentage (%) of the starting activity used in the process under consideration (e.g., synthesis, separation, etc.). Both amounts must refer to the same radionuclide and be decay-corrected to the same time point before calculation (see also Appendix A). It should be understood that according to this definition, the radiochemical yield is only related to the radionuclide under consideration, and it does not include radionuclides that can undergo the same reaction as the radionuclide of interest (e.g., 68 in the68 Compounds labeled with <Ge>. The "radiochemical yield", calculated using the decay-corrected radioactivity values of the product and the starting compound, is the same concept as the "chemical yield". Logically, the decay-corrected reference time must be the same to describe a particular reaction, regardless of whether it is chosen as the end of radionuclide production, the end of bombardment, the start of synthesis, the end of synthesis, or any other convenient reference time point.

[0494] In certain embodiments, the compositions of the present disclosure are characterized by a radiochemical yield ≥ 80% at the end of labeling. In further embodiments, the compositions are characterized by a radiochemical yield ≥ 95% or higher. In further embodiments, the compositions are characterized by a radiochemical yield ≥ 95% at room temperature.

[0495] In certain embodiments, the provided compositions are characterized by a radiochemical yield greater than 85%, such as greater than 85.5%, 86.0%, 86.5%, 87.0%, 87.5%, 88.0%, 88.5%, 89.0%, 89.5%, 90.0%, 90.5%, 91.0%, 91.5%, 92.0%, 92.5%, 93.0%, 93.5%, 94.0%, 94.5%, 95.0%, 95.5%, 96.0%, 96.5%, 97.0%, 97.5%, 98.0%, 98.5%, 99.0% or 99.5%. In certain embodiments, the provided compositions are characterized by a radiochemical yield greater than 90%. In certain embodiments, the provided compositions are characterized by a radiochemical yield greater than 92%. In certain embodiments, the compositions are characterized by a radiochemical yield greater than 95%.

[0496] 4.5.2. Properties of Radionuclide Starting Materials

[0497] By bombarding a target disk comprising a high-purity Nb backing and a target coating comprising stable nickel or zinc isotopes with deuterons, protons or alpha particles and using a particle accelerator (e.g., a medical cyclotron), a high-purity composition comprising one or more copper radionuclides <Cu*> (e.g., 60 <Cu>, 61 <Cu>, 62 <Cu>, 64 <Cu> and 67 <Cu>) is produced. For example, methods for preparing high-purity compositions comprising copper radionuclides are described in U.S. Provisional Patent Application No. 63 / 409,684, filed September 23, 2022, which is hereby incorporated by reference in its entirety into the present application.

[0498] In certain embodiments, the radioactive copper solution comprises radioactive copper dissolved as its chloride salt. In certain embodiments, the irradiated target material is dissolved in an HCl solution. In certain embodiments, the HCl solution is ≥ 4M, ≥ 5M, or ≥ 6M.

[0499] In various embodiments, the radionuclide purity of the radionuclide composition at the end of synthesis (EOB + 2 hours) is ≥ 95.0%. In certain embodiments, the high-purity composition comprises 6X Cu radionuclides, such as 61 Cu, 64 Cu, or 67 Cu. In certain embodiments, the high-purity composition comprises 64 Cu, for example, used as a therapeutic agent. In other embodiments, the high-purity composition comprises 67 Cu. In certain embodiments, the high-purity composition comprises 61 Cu, for example, used as a radiotracer, for example, for diagnostic imaging.

[0500] In various embodiments, the high-purity composition comprises 61 Cu and has a radionuclide purity of ≥ 97.0% at the end of synthesis.

[0501] In certain embodiments, the radionuclide composition, such as a high-purity radionuclide, comprises 61 Cu, 64 Cu, or 67 Cu, particularly 61 Cu, characterized by one or more of the following purity requirements:

[0502] 110m Ag ≤ 0.1 Bq / g;

[0503] 108m Ag ≤ 0.1 Bq / g; and

[0504] 109 Cd ≤ 0.1 Bq / g.

[0505] Considering radioactive cobalt impurities, 64 the Ni(p,α) reaction produces 61 Co (t1 / 2 = 1.649 h), and other radioactive cobalt impurities (e.g., 55 Co, etc.) mainly come from a small amount of other (A ≠ 64) Ni isotopes in the isotopically enriched starting material. However, for 61 Cu, in other reactions with other Ni isotopes, the main 61 Ni(p,α) and 60 Ni(d,α) reactions will produce long-lived58 Co (t1 / 2 = 70.86 d), compared with 61 Cu, produces 0.05% and 0.11% of the 58 Co relative activity, respectively. Therefore, in 61 terms of Cu purification, it may prove more important to efficiently purify the radionuclide composition from radioactive cobalt by-products. When considering 61 the quality control of Cu, Section 2.6 of the International Atomic Energy Agency's Report No. 1 on Radioisotopes and Radiopharmaceuticals [INTERNATIONAL ATOMIC ENERGY AGENCY, CyclotroNproduced radionuclides: EmergingpositroNemitters for medical applications: 64 Cu and 124 I, Radioisotopes andRadiopharmaceuticals Reports 1, IAEA, VienNa (2016) 63, which is incorporated herein by reference in its entirety] details the 64 radionuclide purity and molar activity of Cu.

[0506] In certain embodiments, the high-purity radionuclide composition is produced by deuteron irradiation of natural nickel or 60 Ni, or by proton irradiation of 61 Ni, wherein the composition comprises one or more of the following:

[0507] 56 Co ≤ 1500 Bq / g;

[0508] 57 Co ≤ 100 Bq / g;

[0509] 58 Co ≤ 15000 Bq / g;

[0510] 60 Co ≤ 15 Bq / g.

[0511] In certain embodiments, the high-purity radionuclide composition is produced by deuteron irradiation of natural nickel or 60 Ni, or by proton irradiation of 61 Ni, wherein the composition comprises two or more of the following:

[0512] 56 Co ≤ 1500 Bq / g;

[0513] 57 Co ≤ 100 Bq / g;

[0514] 58 Co ≤ 15000 Bq / g;

[0515] 60 Co ≤ 15 Bq / g; and / or

[0516] having two or more of the following:

[0517] 110m Ag ≤ 1 Bq / g;

[0518] 108m Ag ≤ 1 Bq / g; and

[0519] 109 Cd ≤ 1 Bq / g.

[0520] In certain embodiments, the high-purity radionuclide composition is produced by deuteron irradiation of natural nickel or 60 Ni, or by proton irradiation of 61 Ni, wherein the radionuclide is not a Cu radionuclide, and the composition comprises one or more of the following:

[0521] 110m Ag ≤ 0.1 Bq / g;

[0522] 108m Ag ≤ 0.1 Bq / g; and

[0523] 109 Cd ≤ 0.1 Bq / g.

[0524] 4.5.2.1 Specific Activity of Radionuclides

[0525] Provided is a measurement of the specific activity of the 61 Cu]CuCl2 starting material for producing the pharmaceutical composition of the present disclosure. Methods for determining specific activity are known in the art,

[0526] In certain embodiments, the provided composition is characterized by a specific activity ≥ 0.5 GBq / mg, such as ≥ 1 GBq / mg, ≥ 1.5 GBq / mg, ≥ 2.0 GBq / mg, ≥ 3.0 GBq / mg, ≥ 4.0 GBq / mg, ≥ 5.0 GBq / mg, ≥ 6.0 GBq / mg, ≥ 7.0 GBq / mg, ≥ 8.0 GBq / mg, ≥ 9.0 GBq / mg, or ≥ 10.0 GBq / mg.

[0527] In certain embodiments, the specific activity of the compositions provided in the present application is from 0.5 to 10.0 GBq / mg, such as from 1.0 to 10.0 GBq / mg, from 2.0 to 10.0 GBq / mg, from 3.0 to 10.0 GBq / mg, from 4.0 to 10.0 GBq / mg, from 5.0 to 10.0 GBq / mg, from 6.0 to 10.0 GBq / mg, from 7.0 to 10.0 GBq / mg, from 8.0 to 10.0 GBq / mg, from 9.0 to 10.0 GBq / mg, from 0.5 to 5.0 GBq / mg, from 1.0 to 5.0 GBq / mg, from 2.0 to 5.0 GBq / mg, from 3.0 to 5.0 GBq / mg or from 4.0 to 5.0 GBq / mg.

[0528] In certain embodiments, the specific activity of the compositions provided in the present application is from 0.5 to 1.9 GBq / mg, from 0.55 to 1.85 GBq / mg, from 0.6 to 1.8 GBq / mg, from 0.65 to 1.75 GBq / mg, from 0.7 to 1.7 GBq / mg, from 0.75 to 1.65 GBq / mg, from 0.8 to 1.6 GBq / mg, from 0.85 to 1.55 GBq / mg, from 0.9 to 1.5 GBq / mg, from 0.95 to 1.45 GBq / mg, from 1 to 1.4 GBq / mg, from 1.05 to 1.35 GBq / mg, from 1.1 to 1.3 GBq / mg, from 1.15 to 1.25 GBq / mg, from 0.6 to 1.3 GBq / mg, from 0.65 to 1.25 GBq / mg, from 0.7 to 1.2 GBq / mg, from 0.75 to 1.15 GBq / mg, from 0.8 to 1.1 GBq / mg or from 0.85 to 1.05 GBq / mg.

[0529] In certain embodiments, the compositions provided in the present application have a specific activity of at least 0.5 GBq / mg, such as a specific activity of at least 1 GBq / mg, at least 1.5 GBq / mg, at least 2.0 GBq / mg, at least 3.0 GBq / mg, at least 4.0 GBq / mg, at least 5.0 GBq / mg, at least 6.0 GBq / mg, at least 7.0 GBq / mg, at least 8.0 GBq / mg, at least 9.0 GBq / mg or at least 10.0 GBq / mg.

[0530] In certain embodiments, the specific activity of the compositions provided in the present application is from 0.5 GBq / mg to 10.0 GBq / mg, such as from 1.0 GBq / mg to 10.0 GBq / mg, from 2.0 GBq / mg to 10.0 GBq / mg, from 3.0 GBq / mg to 10.0 GBq / mg, from 4.0 GBq / mg to 10.0 GBq / mg, from 5.0 GBq / mg to 10.0 GBq / mg, from 6.0 GBq / mg to 10.0 GBq / mg, from 7.0 GBq / mg to 10.0 GBq / mg, from 8.0 GBq / mg to 10.0 GBq / mg, from 9.0 GBq / mg to 10.0 GBq / mg, from 0.5 GBq / mg to 5.0 GBq / mg, from 1.0 GBq / mg to 5.0 GBq / mg, from 2.0 GBq / mg to 5.0 GBq / mg, from 3.0 GBq / mg to 5.0 GBq / mg or from 4.0 GBq / mg to 5.0 GBq / mg.

[0531] In certain embodiments, the specific activity of the compositions provided in the present application is from 0.5 GBq / mg to 1.9 GBq / mg, from 0.55 GBq / mg to 1.85 GBq / mg, from 0.6 GBq / mg to 1.8 GBq / mg, from 0.65 GBq / mg to 1.75 GBq / mg, from 0.7 GBq / mg to 1.7 GBq / mg, from 0.75 GBq / mg to 1.65 GBq / mg, from 0.8 GBq / mg to 1.6 GBq / mg, from 0.85 GBq / mg to 1.55 GBq / mg, from 0.9 GBq / mg to 1.5 GBq / mg, from 0.95 GBq / mg to 1.45 GBq / mg, from 1 GBq / mg to 1.4 GBq / mg, from 1.05 GBq / mg to 1.35 GBq / mg, from 1.1 GBq / mg to 1.3 GBq / mg, from 1.15 GBq / mg to 1.25 GBq / mg, from 0.6 GBq / mg to 1.3 GBq / mg, from 0.65 GBq / mg to 1.25 GBq / mg, characterized in that the specific activity is from 0.7 to 1.2 GBq / mg, from 0.75 to 1.25 GBq / mg, from 0.8 to 1.1 GBq / mg or from 0.85 GBq / mg to 1.05 GBq / mg.

[0532] In certain embodiments, the specific activity of the compositions provided in the present application is from 0.7 GBq / mg to 1.2 GBq / mg, from 0.75 GBq / mg to 1.15 GBq / mg, from 0.8 GBq / mg to 1.1 GBq / mg or from 0.85 GBq / mg to 1.05 GBq / mg.

[0533] In certain embodiments, the provided composition is characterized by a specific activity ≥ 0.5 GBq / mg, such as ≥ 1 GBq / mg, ≥ 1.5 GBq / mg, ≥ 2.0 GBq / mg, ≥ 3.0 GBq / mg, ≥ 4.0 GBq / mg, ≥ 5.0 GBq / mg, ≥ 6.0 GBq / mg, ≥ 7.0 GBq / mg, ≥ 8.0 GBq / mg, ≥ 9.0 GBq / mg, or ≥ 10.0 GBq / mg.

[0534] In certain embodiments, the specific activity of the composition provided in the present application is 0.5 to 10.0 GBq / mg, such as 1.0 to 10.0 GBq / mg, 2.0 to 10.0 GBq / mg, 3.0 to 10.0 GBq / mg, 4.0 to 10.0 GBq / mg, 5.0 to 10.0 GBq / mg, 6.0 to 10.0 GBq / mg, 7.0 to 10.0 GBq / mg, 8.0 to 10.0 GBq / mg, 9.0 to 10.0 GBq / mg, 0.5 to 5.0 GBq / mg, 1.0 to 5.0 GBq / mg, 2.0 to 5.0 GBq / mg, 3.0 to 5.0 GBq / mg, or 4.0 to 5.0 GBq / mg.

[0535] In certain embodiments, the specific activity of the composition provided in the present application is 0.5 to 1.9 GBq / mg, 0.55 to 1.85 GBq / mg, 0.6 to 1.8 GBq / mg, 0.65 to 1.75 GBq / mg, 0.7 to 1.7 GBq / mg, 0.75 to 1.65 GBq / mg, 0.8 to 1.6 GBq / mg, 0.85 to 1.55 GBq / mg, 0.9 to 1.5 GBq / mg, 0.95 to 1.45 GBq / mg, 1 to 1.4 GBq / mg, 1.05 to 1.35 GBq / mg, 1.1 to 1.3 GBq / mg, 1.15 to 1.25 GBq / mg, 0.6 to 1.3 GBq / mg, 0.65 to 1.25 GBq / mg, 0.7 to 1.2 GBq / mg, 0.75 to 1.15 GBq / mg, 0.8 to 1.1 GBq / mg, or 0.85 to 1.05 GBq / mg.

[0536] In certain embodiments, the composition provided in the present application has a specific activity of at least 0.5 GBq / mg, such as a specific activity of at least 1 GBq / mg, at least 1.5 GBq / mg, at least 2.0 GBq / mg, at least 3.0 GBq / mg, at least 4.0 GBq / mg, at least 5.0 GBq / mg, at least 6.0 GBq / mg, at least 7.0 GBq / mg, at least 8.0 GBq / mg, at least 9.0 GBq / mg, or at least 10.0 GBq / mg.

[0537] In certain embodiments, the specific activity of the compositions provided in the present application is from 0.5 GBq / mg to 10.0 GBq / mg, such as from 1.0 GBq / mg to 10.0 GBq / mg, from 2.0 GBq / mg to 10.0 GBq / mg, from 3.0 GBq / mg to 10.0 GBq / mg, from 4.0 GBq / mg to 10.0 GBq / mg, from 5.0 GBq / mg to 10.0 GBq / mg, from 6.0 GBq / mg to 10.0 GBq / mg, from 7.0 GBq / mg to 10.0 GBq / mg, from 8.0 GBq / mg to 10.0 GBq / mg, from 9.0 GBq / mg to 10.0 GBq / mg, from 0.5 GBq / mg to 5.0 GBq / mg, from 1.0 GBq / mg to 5.0 GBq / mg, from 2.0 GBq / mg to 5.0 GBq / mg, from 3.0 GBq / mg to 5.0 GBq / mg or from 4.0 GBq / mg to 5.0 GBq / mg.

[0538] In certain embodiments, the specific activity of the compositions provided in the present application is from 0.5 GBq / mg to 1.9 GBq / mg, from 0.55 GBq / mg to 1.85 GBq / mg, from 0.6 GBq / mg to 1.8 GBq / mg, from 0.65 GBq / mg to 1.75 GBq / mg, from 0.7 GBq / mg to 1.7 GBq / mg, from 0.75 GBq / mg to 1.65 GBq / mg, from 0.8 GBq / mg to 1.6 GBq / mg, from 0.85 GBq / mg to 1.55 GBq / mg, from 0.9 GBq / mg to 1.5 GBq / mg, from 0.95 GBq / mg to 1.45 GBq / mg, from 1 GBq / mg to 1.4 GBq / mg, from 1.05 GBq / mg to 1.35 GBq / mg, from 1.1 GBq / mg to 1.3 GBq / mg, from 1.15 GBq / mg to 1.25 GBq / mg, from 0.6 GBq / mg to 1.3 GBq / mg, from 0.65 GBq / mg to 1.25 GBq / mg, characterized in that the specific activity is from 0.7 to 1.2 GBq / mg, from 0.75 to 1.15 GBq / mg, from 0.8 to 1.1 GBq / mg or from 0.85 GBq / mg to 1.05 GBq / mg.

[0539] In certain embodiments, the specific activity of the compositions provided in the present application is from 0.7 GBq / mg to 1.2 GBq / mg, from 0.75 GBq / mg to 1.15 GBq / mg, from 0.8 GBq / mg to 1.1 GBq / mg or from 0.85 GBq / mg to 1.05 GBq / mg.

[0540] In certain embodiments, the provided composition is characterized by a specific activity ≥ 0.5 GBq / μg, such as ≥ 1 GBq / μg, ≥ 1.5 GBq / μg, ≥ 2.0 GBq / μg, ≥ 3.0 GBq / μg, ≥ 4.0 GBq / μg, ≥ 5.0 GBq / μg, ≥ 6.0 GBq / μg, ≥ 7.0 GBq / μg, ≥ 8.0 GBq / μg, ≥ 9.0 GBq / μg or ≥ 10.0 GBq / μg.

[0541] In certain embodiments, the specific activity of the composition provided in the present application is from 0.5 to 10.0 GBq / μg, such as from 1.0 to 10.0 GBq / μg, from 2.0 to 10.0 GBq / μg, from 3.0 to 10.0 GBq / μg, from 4.0 to 10.0 GBq / μg, from 5.0 to 10.0 GBq / μg, from 6.0 to 10.0 GBq / μg, from 7.0 to 10.0 GBq / μg, from 8.0 to 10.0 GBq / μg, from 9.0 to 10.0 GBq / μg, from 0.5 to 5.0 GBq / μg, from 1.0 to 5.0 GBq / μg, from 2.0 to 5.0 GBq / μg, from 3.0 to 5.0 GBq / μg or from 4.0 to 5.0 GBq / μg.

[0542] In certain embodiments, the specific activity of the composition provided in the present application is from 0.5 to 1.9 GBq / μg, from 0.55 to 1.85 GBq / μg, from 0.6 to 1.8 GBq / μg, from 0.65 to 1.75 GBq / μg, from 0.7 to 1.7 GBq / μg, from 0.75 to 1.65 GBq / μg, from 0.8 to 1.6 GBq / μg, from 0.85 to 1.55 GBq / μg, from 0.9 to 1.5 GBq / μg, from 0.95 to 1.45 GBq / μg, from 1 to 1.4 GBq / μg, from 1.05 to 1.35 GBq / μg, from 1.1 to 1.3 GBq / μg, from 1.15 to 1.25 GBq / μg, from 0.6 to 1.3 GBq / μg, from 0.65 to 1.25 GBq / μg, from 0.7 to 1.2 GBq / μg, from 0.75 to 1.15 GBq / μg, from 0.8 to 1.1 GBq / μg or from 0.85 to 1.05 GBq / μg.

[0543] In certain embodiments, the specific activity of the composition provided in the present application is at least 0.5 GBq / μg, such as at least 1 GBq / μg, at least 1.5 GBq / μg, at least 2.0 GBq / μg, at least 3.0 GBq / μg, at least 4.0 GBq / μg, at least 5.0 GBq / μg, at least 6.0 GBq / μg, at least 7.0 GBq / μg, at least 8.0 GBq / μg, at least 9.0 GBq / μg or at least 10.0 GBq / μg.

[0544] In certain embodiments, the specific activity of the compositions provided in the present application is from 0.5 GBq / μg to 10.0 GBq / μg, such as from 1.0 GBq / μg to 10.0 GBq / μg, from 2.0 GBq / μg to 10.0 GBq / μg, from 3.0 GBq / μg to 10.0 GBq / μg, from 4.0 GBq / μg to 1.0 GBq / μg, from 5.0 GBq / μg to 10.0 GBq / μg, from 6.0 GBq / μg to 10.0 GBq / μg, from 7.0 GBq / μg to 10.0 GBq / μg, from 8.0 GBq / μg to 10.0 GBq / μg, from 9.0 GBq / μg to 10.0 GBq / μg, from 0.5 GBq / μg to 5.0 GBq / μg, from 1.0 GBq / μg to 5.0 GBq / μg, from 2.0 GBq / μg to 5.0 GBq / μg, from 3.0 GBq / μg to 5.0 GBq / μg or from 4.0 GBq / μg to 5.0 GBq / μg.

[0545] In certain embodiments, the specific activity of the compositions provided in the present application is from 0.5 GBq / μg to 1.9 GBq / μg, from 0.55 GBq / μg to 1.85 GBq / μg, from 0.6 GBq / μg to 1.8 GBq / μg, from 0.65 GBq / μg to 1.75 GBq / μg, from 0.7 GBq / μg to 1.7 GBq / μg, from 0.75 GBq / μg to 1.65 GBq / μg, from 0.8 GBq / μg to 1.6 GBq / μg, from 0.85 GBq / μg to 1.55 GBq / μg, from 0.9 GBq / μg to 1.5 GBq / μg, from 0.95 GBq / μg to 1.45 GBq / μg, from 1 GBq / μg to 1.4 GBq / μg, from 1.05 GBq / μg to 1.35 GBq / μg, from 1.1 GBq / μg to 1.3 GBq / μg, from 1.15 GBq / μg to 1.25 GBq / μg, from 0.6 GBq / μg to 1.3 GBq / μg, from 0.65 GBq / μg to 1.25 GBq / μg, characterized in that the specific activity is from 0.7 to 1.2 GBq / μg, from 0.75 to 1.15 GBq / μg, from 0.8 to 1.1 GBq / μg or from 0.85 GBq / μg to 1.05 GBq / μg.

[0546] In certain embodiments, the specific activity of the compositions provided in the present application is from 0.7 GBq / μg to 1.2 GBq / μg, from 0.75 GBq / μg to 1.15 GBq / μg, from 0.8 GBq / μg to 1.1 GBq / μg or from 0.85 GBq / μg to 1.05 GBq / μg.

[0547] 4.5.2.2 Chemical Purity

[0548] In certain embodiments, the radionuclide composition is characterized by "chemical purity", which in the present application is understood as the mole percentage of the identified or desired radionuclide to all metals in the sample. The radionuclide composition prepared by the methods disclosed in the present application exhibits high chemical purity, which is beneficial for the production of radiopharmaceuticals with high radiochemical purity. Radiochemical purity, as understood in the present application, is the ratio or percentage of the reactivity of the desired radionuclide in the radiopharmaceutical to the total radioactivity of the sample including the radiopharmaceutical. Non-radioactive isotopes of metals ("cold" metals) do not contribute to the total radioactivity of the sample, but they can compete with the desired radionuclide for inclusion in the radiopharmaceutical, for example, competing for chelation sites in the radiopharmaceutical.

[0549] In certain embodiments, the radionuclide composition according to the present disclosure has a chemical purity of ≥99.0 mole %. In certain embodiments, the radionuclide composition is prepared according to the methods provided in the present application.

[0550] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by one or more of the following:

[0551] Fe ≤ 2 μg / L;

[0552] 69 Cu and 65 The total of Cu ≤ 1 μg / L;

[0553] Zn(II) ≤ 2 μg / L;

[0554] Sn(IV) ≤ 0.01 μg / L;

[0555] Ti(IV) ≤ 0.01 μg / L;

[0556] Al(III) ≤ 2 μg / L;

[0557] As ≤ 1 μg / L;

[0558] Ni ≤ 1 μg / L; and

[0559] wherein any one of Cr, Cd, Co, and Y is ≤ 0.1 μg / mL.

[0560] In certain embodiments, the radionuclide composition is characterized by comprising Fe ≤ 2 μg / L. In certain embodiments, the iron content is ≤ 3 μg / L, ≤ 2.9 μg / L, ≤ 2.8 μg / L, ≤ 2.7 μg / L, ≤ 2.6 μg / L, ≤ 2.5 μg / L, ≤ 2.4 μg / L, ≤ 2.3 μg / L, ≤ 2.2 μg / L, ≤ 2.1 μg / L, ≤ 2 μg / L, ≤ 1.9 μg / L, ≤ 1.8 μg / L, ≤ 1.7 μg / L, ≤ 1.6 μg / L, ≤ 1.5 μg / L, ≤ 1.4 μg / L, ≤ 1.3 μg / L, ≤ 1.2 μg / L, ≤ 1.1 μg / L, ≤ 1 μg / L, ≤ 0.9 μg / L, ≤ 0.8 μg / L, ≤ 0.7 μg / L, ≤ 0.6 μg / L, ≤ 0.5 μg / L, ≤ 0.4 μg / L, ≤ 0.3 μg / L, ≤ 0.2 μg / L or ≤ 0.1 μg / L.

[0561] In certain embodiments, the radionuclide composition is characterized by comprising Cu (non-radioactive) ≤ 1 μg / L. In certain embodiments, the Cu (non-radioactive) content is ≤ 2 μg / L, ≤ 1.9 μg / L, ≤ 1.8 μg / L, ≤ 1.7 μg / L, ≤ 1.6 μg / L, ≤ 1.5 μg / L, ≤ 1.4 μg / L, ≤ 1.3 μg / L, ≤ 1.2 μg / L, ≤ 1.1 μg / L, ≤ 1 μg / L, ≤ 0.9 μg / L, ≤ 0.8 μg / L, ≤ 0.7 μg / L, ≤ 0.6 μg / L, ≤ 0.5 μg / L, ≤ 0.4 μg / L, ≤ 0.3 μg / L, ≤ 0.2 μg / L or ≤ 0.1 μg / L.

[0562] In certain embodiments, the radionuclide composition is characterized by comprising Ni ≤ 1 μg / L. In certain embodiments, the nickel content is ≤ 4.5 μg / L, ≤ 4.4 μg / L, ≤ 4.3 μg / L, ≤ 4.2 μg / L, ≤ 4.1 μg / L, ≤ 4 μg / L, ≤ 3.9 μg / L, ≤ 3.8 μg / L, ≤ 3.7 μg / L, ≤ 3.6 μg / L, ≤ 3.5 μg / L, ≤ 3.4 μg / L, ≤ 3.3 μg / L, ≤ 3.2 μg / L, ≤ 3.1 μg / L, ≤ 3 μg / L, ≤ 2.9 μg / L, ≤ 2.8 μg / L, ≤ 2.7 μg / L, ≤ 2.6 μg / L, ≤ 2.5 μg / L, ≤ 2.4 μg / L, ≤ 2.3 μg / L, ≤ 2.2 μg / L, ≤ 2.1 μg / L, ≤ 2 μg / L, ≤ 1.9 μg / L, ≤ 1.8 μg / L, ≤ 1.7 μg / L, ≤ 1.6 μg / L, ≤ 1.5 μg / L, ≤ 1.4 μg / L, ≤ 1.3 μg / L, ≤ 1.2 μg / L, ≤ 1.1 μg / L, ≤ 1 μg / L, ≤ 0.9 μg / L, ≤ 0.8 μg / L, ≤ 0.7 μg / L, ≤ 0.6 μg / L, ≤ 0.5 μg / L, ≤ 0.4 μg / L, ≤ 0.3 μg / L, ≤ 0.2 μg / L or ≤ 0.1 μg / L.

[0563] In certain embodiments, the radionuclide composition is an embodiment as described above, further characterized by one or more of the following: a radioactivity concentration at EoB + 2 hours of 0.60 - 0.66 GBq / mL; a molar activity at EoB + 2 hours of 10 - 100 MBq / nmol; and an activity at EoB + 2 hours of > 500 MBq. An embodiment as described above, further characterized by one or more of the following: a radioactivity concentration at EoB + 2 hours of > 25 MBq / mL, a molar activity at EoB + 2 hours of 10 - 150 MBq / nmol, and an activity at EoB + 2 hours of > 150 MBq.

[0564] An embodiment as described above, further characterized by one or more of the following: a radioactivity concentration at EoB + 2 hours of 0.60 - 0.66 GBq / mL; a molar activity at EoB + 2 hours of 10 - 100 MBq / nmol; and an activity at the end of synthesis of > 500 MBq.

[0565] 4.5.3. Radioactivity Concentration

[0566] The radioactivity concentration is the total radioactivity per unit volume 61 of the

[0567] In certain embodiments, ≥ 0.5 GBq / mL, such as ≥ 1 GBq / mL, ≥ 1.5 GBq / mL, ≥ 2.0 GBq / mL, ≥ 3.0 GBq / mL, ≥ 4.0 GBq / mL, ≥ 5.0 GBq / mL, ≥ 6.0 GBq / mL, ≥ 7.0 GBq / mL, ≥ 8.0 GBq / mL, ≥ 9.0 GBq / mL, or ≥ 10.0 GBq / mL.

[0568] In certain embodiments, the provided composition is characterized by a radioactivity concentration of 0.5 to 10.0 GBq / mL, such as 1.0 to 10.0 GBq / mL, 2.0 to 10.0 GBq / mL, 3.0 to 10.0 GBq / mL, 4.0 to 10.0 GBq / mL, 5.0 to 10.0 GBq / mL, 6.0 to 10.0 GBq / mL, 7.0 to 10.0 GBq / mL, 8.0 to 10.0 GBq / mL, 9.0 to 10.0 GBq / mL, 0.5 to 5.0 GBq / mL, 1.0 to 5.0 GBq / mL, 2.0 to 5.0 GBq / mL, 3.0 to 5.0 GBq / mL, or 4.0 to 5.0 GBq / mL.

[0569] In certain embodiments, the provided composition is characterized by a radioactivity concentration of 0.5 to 1.9 GBq / mL, 0.55 to 1.85 GBq / mL, 0.6 to 1.8 GBq / mL, 0.65 to 1.75 GBq / mL, 0.7 to 1.7 GBq / mL, 0.75 to 1.65 GBq / mL, 0.8 to 1.6 GBq / mL, 0.85 to 1.55 GBq / mL, 0.9 to 1.5 GBq / mL, 0.95 to 1.45 GBq / mL, 1 to 1.4 GBq / mL, 1.05 to 1.35 GBq / mL, 1.1 to 1.3 GBq / mL, 1.15 to 1.25 GBq / mL, 0.6 to 1.3 GBq / mL, 0.65 to 1.25 GBq / mL, 0.7 to 1.2 GBq / mL, 0.75 to 1.15 GBq / mL, 0.8 to 1.1 GBq / mL, or 0.85 to 1.05 GBq / mL.

[0570] In certain embodiments, the provided pharmaceutical preparation composition is characterized by a radioactivity concentration of 0.3 to 0.75 GBq / mL.

[0571] The radioactive concentration of the resulting pharmaceutical composition will be diluted 3 to 10 times, provided that the radioactive concentration ≥ 8 MBq / mL. In certain embodiments, the provided composition is characterized by a radioactive concentration of 8 to 20 MBq / mL, 9 to 19 MBq / mL, 10 to 18 MBq / mL, 11 to 19 MBq / mL, 12 to 18 MBq / mL, 13 to 15 MBq / mL, 14 to 15 MBq / mL, 8 to 14 MBq / mL, 8 to 13 MBq / mL, 8 to 12 MBq / mL, 8 to 11 MBq / mL, 8 to 10 MBq / mL, 8 to 9 MBq / mL, 9 to 14 MBq / mL, 10 to 13 MBq / mL, or 11 to 12 MBq / mL.

[0572] 4.6. Enumerated embodiments

[0573] Group A of the enumerated embodiments

[0574] Embodiment 1a: A compound, wherein the compound has the formula X*:

[0575]

[0576] or a pharmaceutically acceptable salt thereof,

[0577] wherein:

[0578] the chelating moiety is NODAGA;

[0579] *Cu is 61 Cu or 67 Cu;

[0580] L is

[0581] V is a targeting moiety that binds to PSMA;

[0582] n is 1;

[0583] m is 1; and

[0584] p 1.

[0585] Embodiment 1b: A compound of any of the foregoing embodiments, wherein the compound has the formula X:

[0586]

[0587] or a pharmaceutically acceptable salt thereof,

[0588] wherein:

[0589] the chelating moiety is NODAGA;

[0590] *Cu is selected from 61 Cu,62 Cu, 64 Cu and 67 a copper radionuclide of Cu;

[0591] L is

[0592] V is a targeting moiety that binds to PSMA;

[0593] n is 1;

[0594] m is 1; and

[0595] p is 1.

[0596] Embodiment 1. A compound of any of the foregoing embodiments, wherein the compound has Formula 10:

[0597]

[0598] or a pharmaceutically acceptable salt thereof;

[0599] wherein V comprises a targeting moiety that binds to PSMA.

[0600] Embodiment 2. A compound of any of the foregoing embodiments, wherein V comprises a means for binding to PSMA.

[0601] Embodiment 3. A compound of any of the foregoing embodiments, wherein V comprises the following structure:

[0602]

[0603] Embodiment 4. A compound of any of the foregoing embodiments, wherein the compound has the following structure:

[0604]

[0605] or a pharmaceutically acceptable salt thereof.

[0606] Embodiment 5. A compound of any of the foregoing embodiments, wherein the compound has the following structure:

[0607]

[0608] or a pharmaceutically acceptable salt thereof.

[0609] Embodiment 6a: A compound of any of the foregoing embodiments, wherein the compound has Formula X*:

[0610]

[0611] or a pharmaceutically acceptable salt thereof,

[0612] wherein:

[0613] The chelating moiety is NODAGA;

[0614] *Cu is selected from 61 Cu, 62 Cu, 64 Cu and 67 a copper radionuclide of Cu;

[0615] L is

[0616] V is a targeting moiety that binds to PSMA;

[0617] n is 1;

[0618] m is 1; and

[0619] p is 1.

[0620] Embodiment 6. A compound of any of the foregoing embodiments, which comprises a copper atom chelated by the compound of Embodiment 1, wherein the compound has the structure of Formula 10*:

[0621]

[0622] or a pharmaceutically acceptable salt thereof;

[0623] wherein *Cu is selected from 61 Cu, 62 Cu, 64 Cu and 67 a copper radionuclide of Cu.

[0624] Embodiment 7. The compound of Example 6a or 6, wherein *Cu is 61 Cu.

[0625] Embodiment 8. The compound of Example 6a or 6, wherein *Cu is 67 Cu.

[0626] Embodiment 9. The compound of any of the foregoing embodiments, wherein V comprises the following structure:

[0627]

[0628] Embodiment 10. The compound of Embodiments 1-6 and 8-9, wherein the compound has the following structure:

[0629]

[0630] or a pharmaceutically acceptable salt thereof.

[0631] Embodiment 11. The compounds of Embodiments 1-7 and 9, wherein the compound has the following structure:

[0632]

[0633] or a pharmaceutically acceptable salt thereof.

[0634] Embodiment 12. The compound of Embodiment 10, wherein the compound has the following structure:

[0635]

[0636] or a pharmaceutically acceptable salt thereof.

[0637] Embodiment 13. The compound of Embodiment 11, wherein the compound has the following structure:

[0638]

[0639] or a pharmaceutically acceptable salt thereof.

[0640] Embodiment 14. A pharmaceutical composition comprising the compound of any one of the foregoing embodiments and a pharmaceutically acceptable excipient, wherein the composition is characterized by one or more of the following:

[0641] Molar activity ≥ 3 MBq / nmol;

[0642] Radiochemical purity ≥ 91%;

[0643] Radioactive concentration ≥ 8 MBq / mL;

[0644] Radionuclide purity of the compound at the end of synthesis (EoB + 2 hours) ≥ 95%; and

[0645] pH is 4 - 7.

[0646] Embodiment 15. The composition of any one of the foregoing embodiments, wherein the composition is characterized by a molar activity ≥ 3 MBq / nmol, such as ≥ 10 MBq / nmol, 10 to 250 MBq / nmol, 20 to 250 MBq / nmol, 50 to 250 MBq / nmol, 50 to 200 MBq / nmol, 50 to 150 MBq / nmol, 50 to 100 MBq / nmol, 100 to 250 MBq / nmol, 100 to 150 MBq / nmol, 150 to 250 MBq / nmol, 150 to 200 MBq / nmol or 200 to 250 MBq / nmol.

[0647] Embodiment 16. The composition of any of the foregoing embodiments, wherein the composition is characterized by a radiochemical purity of ≥91%, such as ≥95%, ≥95.5%, ≥96%, ≥96.5%, ≥97%, ≥97.5%, ≥98%, ≥98.5%, ≥99% or ≥99.5%.

[0648] Embodiment 17. The composition of any of the foregoing embodiments, wherein the composition is characterized by a radioactive concentration of ≥8 MBq / mL, such as 8 to 400 MBq / mL, 8 to 350 MBq / mL, 8 to 300 MBq / mL, 8 to 250 MBq / mL, 8 to 200 MBq / mL, 8 to 150 MBq / mL, 8 to 100 MBq / mL, 8 to 100 MBq / mL, 8 to 50 MBq / mL, 8 to 25 MBq / mL or 8 to 15 MBq / mL.

[0649] Embodiment 18. The composition of any of the foregoing embodiments, wherein the composition is characterized by a radionuclide purity of the compound at the end of synthesis of ≥95%, such as ≥95.5%, ≥96%, ≥96.5%, ≥97%, ≥97.5%, ≥98%, ≥98.5%, ≥99%, ≥99.1%, ≥99.2%, ≥99.3%, ≥99.4%, ≥99.5%, ≥99.6%, ≥99.7%, ≥99.8%, ≥99.9% or ≥99.99%.

[0650] Embodiment 19. The composition of any of the foregoing embodiments, wherein the composition is characterized by a radionuclide purity of the total radioactive cobalt compounds at the end of synthesis (EoB plus 2 hours) of ≤0.05%, such as ≤0.04%, ≤0.03%, ≤0.02% or ≤0.01%.

[0651] Embodiment 20. The composition of any of the foregoing embodiments, wherein the composition is characterized by a pH of 4 - 7.

[0652] Embodiment 21. A composition comprising the compound of any of the foregoing embodiments and a pharmaceutically acceptable excipient, wherein the composition is characterized by one or more of the following:

[0653] A molar activity of ≥20 MBq / nmol;

[0654] A radiochemical purity of ≥91%;

[0655] A radioactive concentration of 8 to 100 MBq / mL;

[0656] A radionuclide purity of the compound at the end of synthesis (EoB plus 2 hours) of ≥95%; and

[0657] A pH of 4 - 7.

[0658] Embodiment 22. The composition of any of the foregoing embodiments, wherein the composition is characterized by a molar activity ≥ 20 MBq / nmol, such as 20 to 250 MBq / nmol, 50 to 250 MBq / nmol, 50 to 200 MBq / nmol, 50 to 150 MBq / nmol, 50 to 100 MBq / nmol, 100 to 250 MBq / nmol, 100 to 150 MBq / nmol, 150 to 250 MBq / nmol, 150 to 200 MBq / nmol, or 200 to 250 MBq / nmol.

[0659] Embodiment 23. The composition of any of the foregoing embodiments, wherein the composition is characterized by a radiochemical purity ≥ 91%, such as ≥ 95%, ≥ 95.5%, ≥ 96.0%, ≥ 96.5%, ≥ 97.0%, ≥ 97.5%, ≥ 98.0%, ≥ 98.5%, ≥ 99.0%, or ≥ 99.5%.

[0660] Embodiment 24. The composition of any of the foregoing embodiments, wherein the composition is characterized by a radioactive concentration of 8 to 100 MBq / mL, such as 8 to 15 MBq / mL.

[0661] Embodiment 25. The composition of any of the foregoing embodiments, wherein the composition is characterized by a radionuclide purity of the radionuclide compound at the end of synthesis ≥ 95.0%, such as ≥ 95.5%, ≥ 96%, ≥ 96.5%, ≥ 97%, ≥ 97.5%, ≥ 98%, ≥ 98.5%, ≥ 99%, ≥ 99.1%, ≥ 99.2%, ≥ 99.3%, ≥ 99.4%, ≥ 99.5%, ≥ 99.6%, ≥ 99.7%, ≥ 99.8%, or ≥ 99.9%.

[0662] Embodiment 26. The composition of any of the foregoing embodiments, wherein the composition is characterized by a radionuclide purity of the total radioactive cobalt compounds at the end of synthesis (EoB plus 2 hours) ≤ 0.05%, such as ≤ 0.04%, ≤ 0.03%, ≤ 0.02%, or ≤ 0.01%.

[0663] Embodiment 27. A method of generating one or more images of a subject, comprising:

[0664] administering to the subject an effective amount of the composition according to Embodiment 14; and

[0665] generating one or more images of at least a portion of the subject's body.

[0666] Embodiment 28. The method of Embodiment 27, wherein one or more images are generated using positron emission tomography (PET) or single photon emission computed tomography (SPECT).

[0667] Embodiment 29. A method of treating a cancer patient, comprising administering to the patient an effective amount of the composition of Embodiment 21.

[0668] Embodiment 30. A therapeutic diagnostic method, comprising:

[0669] (a) administering to the subject an effective amount of the composition according to Embodiment 14;

[0670] (b) generating one or more images of at least a part of the subject's body; and

[0671] (c) administering to the subject an effective amount of a composition comprising a compound of any of the foregoing embodiments.

[0672] Group B of the recited embodiments

[0673] Example 1a. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable excipient, wherein the compound has formula X*:

[0674]

[0675] or a pharmaceutically acceptable salt thereof,

[0676] wherein: the chelating moiety is NODAGA;

[0677] *Cu is selected from 61 Cu, 62 Cu, 64 Cu and 67 Cu copper radionuclides;

[0678] L is a linking moiety; V is a targeting moiety SST that binds to SSTR; n is 1; m is 1; p is 1.

[0679] Embodiment 1. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable excipient, wherein the compound has formula 20:

[0680]

[0681] or a pharmaceutically acceptable salt thereof;

[0682] wherein:

[0683] *Cu is selected from 61 Cu, 62 Cu and 67 Cu copper radionuclides;

[0684] L is a key or linking group moiety; and

[0685] SST is a targeting moiety that binds to a somatostatin receptor.

[0686] Embodiment 2. The composition of Embodiment 1, wherein the composition is characterized by one or more of the following:

[0687] Molar activity ≥ 3 MBq / nmol;

[0688] Radiochemical purity ≥ 91%;

[0689] Radioactivity concentration ≥ 8 MBq / mL;

[0690] Radionuclide purity of the compound at the end of synthesis (EoB plus 2 hours) ≥ 95%; and

[0691] pH value is 4 - 7.

[0692] Embodiment 3. The composition of any of the preceding embodiments, wherein the composition is characterized by a molar activity ≥ 3 MBq / nmol, such as ≥ 10 MBq / nmol, 10 to 250 MBq / nmol, 20 to 250 MBq / nmol, 50 to 250 MBq / nmol, 50 to 200 MBq / nmol, 50 to 150 MBq / nmol, 50 to 100 MBq / nmol, 100 to 250 MBq / nmol, 100 to 150 MBq / nmol, 150 to 250 MBq / nmol, 150 to 200 MBq / nmol or 200 to 250 MBq / nmol.

[0693] Embodiment 4. The composition of any of the preceding embodiments, wherein the composition is characterized by a radiochemical purity ≥ 91%, such as ≥ 95%, ≥ 95.5%, ≥ 96%, ≥ 96.5%, ≥ 97%, ≥ 97.5%, ≥ 98%, ≥ 98.5%, ≥ 99% or ≥ 99.5%.

[0694] Embodiment 5. The composition of any of the preceding embodiments, wherein the composition is characterized by a radioactivity concentration ≥ 8 MBq / mL, such as 8 to 400 MBq / mL, 8 to 350 MBq / mL, 8 to 300 MBq / mL, 8 to 250 MBq / mL, 8 to 200 MBq / mL, 8 to 150 MBq / mL, 8 to 100 MBq / mL, 8 to 100 MBq / mL, 8 to 50 MBq / mL, 8 to 25 MBq / mL or 8 to 15 MBq / mL.

[0695] Embodiment 6. The composition of any of the foregoing embodiments, wherein the composition is characterized in that the radionuclide purity of the compound at the end of synthesis is ≥95%, such as ≥95.5%, ≥96%, ≥96.5%, ≥97%, ≥97.5%, ≥98%, ≥98.5%, ≥99%, ≥99.1%, ≥99.2%, ≥99.3%, ≥99.4%, ≥99.5%, ≥99.6%, ≥99.7%, ≥99.8%, ≥99.9% or ≥99.99%.

[0696] Embodiment 7. The composition of any of the foregoing embodiments, wherein the composition is characterized in that the pH value is 4 - 7.

[0697] Embodiment 8. The composition of any of the foregoing embodiments, wherein the SST contains a tool for binding to the somatostatin receptor.

[0698] Embodiment 9. The composition of any of the foregoing embodiments, wherein the SST contains the following structure:

[0699]

[0700] Embodiment 10. The composition of any of the foregoing embodiments, wherein the SST contains the following structure:

[0701]

[0702] Embodiment 11. The composition of any of the foregoing embodiments, wherein the compound has the following structure:

[0703]

[0704] or a pharmaceutically acceptable salt thereof.

[0705] Embodiment 12. The composition of any of the foregoing embodiments, wherein the compound has the following structure:

[0706]

[0707] or is a pharmaceutically acceptable salt thereof.

[0708] Embodiment 13. The composition of any of the foregoing embodiments, wherein the compound has the following structure:

[0709]

[0710] or is a pharmaceutically acceptable salt thereof.

[0711] Embodiment 14. The composition of any of the foregoing embodiments, wherein the compound has the following structure:

[0712]

[0713] or a pharmaceutically acceptable salt thereof.

[0714] Embodiment 15. A method of generating one or more images of a subject, comprising:

[0715] (a) administering to the subject an effective amount of the composition according to Embodiment 11; and

[0716] (b) generating one or more images of at least a portion of the subject's body.

[0717] Embodiment 16. The method of Embodiment 14, wherein one or more images are generated using positron emission tomography (PET).

[0718] Embodiment 17. The method of Embodiment 14, wherein one or more images are generated using single photon emission computed tomography (SPECT).

[0719] Embodiment 18. A theranostic method, comprising:

[0720] (a) administering to a subject an effective amount of a first pharmaceutical composition, wherein the composition is the composition according to Embodiment 11;

[0721] (b) generating one or more images of at least a portion of the subject's body;

[0722] (c) administering to the subject an effective amount of a second pharmaceutical composition comprising a compound, wherein the compound is the compound of Formula 20 as defined in Embodiment 1 or a pharmaceutically acceptable salt thereof.

[0723] Listed Embodiments Group C

[0724] Embodiment 1. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable excipient, wherein the compound has Formula 30:

[0725]

[0726] Wherein:

[0727] R 1 is R a ;

[0728] R 2 and R 3 each independently is R a or together with the nitrogen atom to which they are attached form a C 2-9 heterocycle;

[0729] R a each occurrence is independently selected from H, C1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 2-9 heterocyclic group or C 5-9 heteroaryl, which is optionally substituted with one or more substituents selected from -OH, -OR', ═O, ═S, -SH, -SR', -NH2, -NHR', -N(R')2, -NHCOR', -NR'COR', halogen, -CN, -CO2H, -CO2R', -CHO, -COR', -CONH2, -CONHR', -CON(R')2, -NO2, -OP(O)(OH)2, -SO3H, -SO3R', -SOR' and -SO2R', wherein each occurrence of R' is independently C 1-10 alkyl or C 3-10 cycloalkyl;

[0730] n is an integer from 1 to 20;

[0731] m is an integer from 1 to 20; and

[0732] *Cu is selected from 61 Cu, 62 Cu, 64 Cu and 67 Cu radioisotopes;

[0733] or a pharmaceutically acceptable salt thereof; and

[0734] wherein the composition is characterized by one or more of the following:

[0735] molar activity ≥ 3 MBq / nmol;

[0736] radiochemical purity ≥ 91%;

[0737] radioactive concentration ≥ 8 MBq / mL; and

[0738] the radionuclide purity of the compound at the end of synthesis (EoB + 2 hours) ≥ 95%.

[0739] Embodiment 2. The composition of Embodiment 1, wherein R 1 is methyl or H.

[0740] Embodiment 3. The composition of Embodiment 1 or 2, wherein R 2 is H and R 3 is H.

[0741] Embodiment 4. The composition of Embodiment 1 or 2, wherein R 2 and R 3Together with the nitrogen atom to which they are attached, form a C 2-9 heterocycle.

[0742] Embodiment 5. The composition of Embodiment 4, wherein C 2-9 heterocycle is a 6-membered heterocycle selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazane, 1,2,4-triazane and 1,3,5-triazane.

[0743] Embodiment 6. The composition of any one of Embodiments 1-5, wherein the radionuclide is selected from 61 Cu and 67 Cu.

[0744] Embodiment 7. The composition of any one of Embodiments 1-6, wherein the compound has Formula 30a or Formula 30b:

[0745]

[0746] 1 is H or methyl.

[0747] Embodiment 8. The composition of Embodiment 7, wherein the radionuclide is selected from 61 Cu and 67 Cu.

[0748] Embodiment 10. The composition of any one of Embodiments 1-9, wherein the compound is selected from:

[0749]

[0750]

[0751] or a pharmaceutically acceptable salt thereof.

[0752] Embodiment 11. The composition of any one of Embodiments 1-10, wherein the molar activity of the composition is ≥ 3 MBq / nmol, such as ≥ 10 MBq / nmol, 10 to 250 MBq / nmol, 20 to 250 MBq / nmol, 50 to 250 MBq / nmol, 50 to 200 MBq / nmol, 50 to 150 MBq / nmol, 50 to 100 MBq / nmol, 100 to 250 MBq / nmol, 100 to 150 MBq / nmol, 150 to 250 MBq / nmol, 150 to 200 MBq / nmol or 200 to 250 MBq / nmol.

[0753] ​Embodiment 12. A composition according to any one of Embodiments 1-11, wherein the composition has a radiochemical purity of ≥91%, such as ≥95%, ≥95.5%, ≥96%, ≥96.5%, ≥97%, ≥97.5%, ≥98%, ≥98.5%, ≥99% or ≥99.5%.

[0754] Embodiment 13. A composition according to any one of Embodiments 1-12, wherein the composition has a radioactive concentration of ≥8 MBq / mL, such as 8 to 400 MBq / mL, 8 to 350 MBq / mL, 8 to 300 MBq / mL, 8 to 250 MBq / mL, 8 to 200 MBq / mL, 8 to 150 MBq / mL, 8 to 100 MBq / mL, 8 to 100 MBq / mL, 8 to 50 MBq / mL, 8 to 25 MBq / mL or 8 to 15 MBq / mL.

[0755] Embodiment 14. A composition according to any one of Embodiments 1-13, wherein the composition is characterized in that the radionuclide purity of the compound at the end of synthesis is ≥95%, such as ≥95.5%, ≥96%, ≥96.5%, ≥97%, ≥97.5%, ≥98%, ≥98.5%, ≥99%, ≥99.1%, ≥99.2%, ≥99.3%, ≥99.4%, ≥99.5%, ≥99.6%, ≥99.7%, ≥99.8%, ≥99.9% or ≥99.99%.

[0756] Embodiment 15. A composition according to any one of Embodiments 1-14, wherein the composition has a pH of 4 to 7.

[0757] Embodiment 16. A method for generating one or more images of a subject, comprising:

[0758] administering to the subject an effective amount of a composition according to any one of Embodiments 1-15, wherein the radionuclide is 61 Cu; and

[0759] generating one or more images of at least a part of the subject's body.

[0760] Embodiment 17. The method according to Embodiment 16, wherein one or more images are generated using positron emission tomography (PET), PET-computed tomography (PET-CT) or single photon emission computed tomography (SPECT).

[0761] Embodiment 18. The method according to Embodiment 16 or 17, wherein one or more images are generated using PET-CT.

[0762] Embodiment 19. A method of treating a disease in a patient in need thereof, comprising administering to the patient an effective amount of the composition of Embodiment 1, wherein the radionuclide is 67 Cu.

[0763] Embodiment 20. The method of Embodiment 19, wherein the disease is selected from cancer, inflammatory diseases, infectious diseases, and immune diseases.

[0764] Embodiment 21. The method of Embodiment 19 or 20, wherein the disease is cancer.

[0765] Embodiment 22. The method of Embodiment 20 or 21, wherein the cancer is selected from breast cancer, pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer, head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumors, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary origin), thymic cancer, fibroma, glioma, astrocytoma, cervical cancer, and prostate cancer.

[0766] Embodiment 23. A diagnostic method for treatment, comprising:

[0767] (a) Administering to a subject an effective amount of a first pharmaceutical composition, wherein the composition is the composition according to Embodiment 1, wherein the radionuclide is 61 Cu;

[0768] (b) Generating one or more images of the subject; and

[0769] (c) Administering to the subject an effective amount of a second pharmaceutical composition comprising a compound, wherein the compound has Formula 30:

[0770]

[0771] Wherein:

[0772] R 1 is R a ;

[0773] R 2 and R 3 each is independently R a or together with the nitrogen atom to which they are attached form a C 2-9 heterocycle;

[0774] R a each occurrence is independently selected from H, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10 cycloalkyl, C6-10 aryl, C 2-9 heterocyclyl or C 5-9 heteroaryl, optionally substituted by one or more substituents selected from -OH, -OR', =O, =S, -SH, -SR', -NH2, -NHR', -N(R')2, -NHCOR', -NR'COR', halogen, -CN, -CO2H, -CO2R', -CHO, -COR', -CONH2, -CONHR', -CON(R')2, -NO2, -OP(O)(OH)2, -SO3H, -SO3R', -SOR' and -SO2R', wherein each occurrence of R' is independently C 1-10 alkyl or C 3-10 cycloalkyl;

[0775] n is an integer from 1 to 20;

[0776] m is an integer from 1 to 20; and

[0777] *Cu is 67 Cu,

[0778] or a pharmaceutically acceptable salt thereof.

[0779] Embodiment 24. The method of Embodiment 23, wherein:

[0780] (a) the compound of the first pharmaceutical composition is 61 [Cu]Cu-NODAGA-F1 and the compound of the second pharmaceutical composition is 67 [Cu]Cu-NODAGA-F1;

[0781] (b) the compound of the first pharmaceutical composition is 61 [Cu]Cu-NODAGA-F2 and the compound of the second pharmaceutical composition is 67 [Cu]Cu-NODAGA-F2;

[0782] (c) the compound of the first pharmaceutical composition is 61 [Cu]Cu-NODAGA-F3 and the compound of the second pharmaceutical composition is 67 [Cu]Cu-NODAGA-F3; or

[0783] (d) the compound of the first pharmaceutical composition is 61 [Cu]Cu-NODAGA-F4 and the compound of the second pharmaceutical composition is 67 [Cu]Cu-NODAGA-F4.

[0784] Embodiment 25. The method of Embodiment 23 or 24, further comprising based on the first compound 61 the presence or absence of localization of the Cu radionuclide in the subject, via one or more images of the subject, to determine the presence or absence of a disease in the subject.

[0785] Embodiment 26. The method of Embodiment 25, wherein the disease is selected from cancer, inflammatory diseases, infectious diseases, and immune diseases.

[0786] Embodiment 27. The method of any one of Embodiments 23-27, wherein one or more images are generated by using positron emission tomography (PET), PET-computed tomography (PET-CT), or single photon emission computed tomography (SPECT).

[0787] Embodiment 28. A method of preparing the composition of Embodiment 1, comprising combining a high-purity radioactive copper solution with a compound of Formula 40:

[0788]

[0789] wherein R 1 is R a ;

[0790] R 2 and R 3 each is R a or together with the nitrogen atom to which they are attached form a C 2-9 heterocycle;

[0791] R a each occurrence is independently selected from H, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 2-9 heterocyclic group, or C 5-9 heteroaryl, which is optionally substituted with one or more substituents selected from -OH, -OR', =O, =S, -SH, -SR', -NH2, -NHR', -N(R')2, -NHCOR', -NR'COR', halogen, -CN, -CO2H, -CO2R', -CHO, -COR', -CONH2, -CONHR', -CON(R')2, -NO2, -OP(O)(OH)2, -SO3H, -SO3R', -SOR', and -SO2R', where R' each occurrence is independently C 1-10 alkyl or C 3-10 cycloalkyl;

[0792] n is an integer from 1 to 20;

[0793] m is an integer from 1 to 20; and

[0794] The high-purity radioactive copper solution is characterized by one or more of the following:

[0795] The chemical purity is ≥99% in moles and / or:

[0796] Fe ≤ 2 mg / L;

[0797] 69 Cu and 65 The total of Cu ≤ 1 mg / L;

[0798] ZN ≤ 2 mg / L;

[0799] SN ≤ 0.01 mg / L;

[0800] Ti ≤ 0.01 mg / L;

[0801] Al ≤ 2 mg / L;

[0802] As ≤ 1 mg / L;

[0803] Ni ≤ 1 mg / L; and

[0804] wherein any one of Cr, Cd, Co and Y ≤ 0.1 mg / mL.

[0805] Embodiment 29. The method of Embodiment 28, wherein the high-purity radioactive copper solution is 61 Cu]CuCl2.

[0806] Embodiment 30. The method of Embodiment 28 or 29, wherein the high-purity radioactive copper solution and the compound of formula 40 are combined at a temperature of 80 - 95 °C. 5. Examples

[0807] Overview of experimental observations

[0808] Given the increasing clinical demand for PSMA-targeted PET imaging, the production capacity of 68 Ga tracers (2 - 3 patient doses) generated by the generator is very limited. 18 F-labeled derivatives are an alternative, but this comes at the cost of the possibility of radiolabeling and therapeutic companions (theranostics) based on simple chelating agents; 18 F does not provide an option. In addition, 18 Concerns are raised about the defects of F-PSMA radiotracers. 61 Cu can be produced on a large scale in a cyclotron, allowing kit-based radiolabeling, and due to its longer half-life, its distribution radius is greater than 68Ga or 18 F. In addition, compared with existing PSMA radiotracers, this enables delayed imaging, which can lead to improved image contrast without imposing an additional radiation burden on the patient.

[0809] As a proof of concept, 61 Cu was chelated to a targeting moiety (such as PSMA-I&T, SS analog, or FAP inhibitor) via a chelator (such as NODAGA) and a linker moiety. It is reported in this application that the targeting chelator construct can be labeled with 61 Cu within minutes at room temperature, making the procedure for producing PET radiotracers rapid and simple, following a "mix and shake" method without the need for expensive infrastructure such as modular assisted radioactive synthesis or purification systems (commonly used for 18 F and typically used for 68 Ga radiotracers). This method provides increased flexibility for radiopharmacists / practitioners to produce multiple (more than three) patient doses on-site with a batch of 61 Cu in a single working day (in sharp contrast to 68 Ga, where at most 1 - 3 doses can be produced).

[0810] Via the NODAGA chelator, constructs with the same targeting moiety (PSMA-I&T, somatostatin analog, or FAP inhibitor) can be conjugated to form a radiotracer that contains a therapeutic radionuclide of the same chemical element, namely 67 Cu, 67 Cu is a β-emitter and can be used for radiotherapy. Since it belongs to the same chemical element, 67 Cu can bind to the chelator and the targeting moiety in a very similar chemical manner as 61 Cu. This results in co-radiotracers with chemically identical forms of radiotherapy 67 Cu]Cu-NODAGA-PSMA-I&T, 67 Cu]Cu-NODAGA-LM3, 67 Cu]Cu-NODAGA-F1, 67 Cu]Cu-NODAGA-F2, 67 Cu]Cu-NODAGA-F3, 67 Cu]Cu-NODAGA-F4, and 67 Cu]Cu-NODAGA-FAPI-46. These therapeutic compounds have the same properties and systemic distribution as the PET radiotracer, including antigen-targeted lesions. In addition, compared with 177 Lu, 67 Cu has a shorter half-life (t 1 / 267 Cu = 2.6 days relative to 177 Lu = 6.7 days), while having very similar energies of β particles. Thus, 67 Cu may better fit the pharmacokinetics of the proposed tracer, which allows for shorter time intervals between treatment cycles, and last but not least, it is expected to have a lower radiation burden on patients and better logistics in hospital waste management.

[0811] High purity 61 Cu]CuCl2

[0812] Due to the relatively short half-life (t 1 / 2 68 Ga = 68 minutes; 18 F = 110 minutes) and physical characteristics of the radionuclide, the key challenges faced by the PET tracer industry remain a) imaging quality, b) the reliability of supplying and distributing radiopharmaceuticals at low cost, and c) the low radiation burden on patients. Using 61 Cu as a positron emitter (e.g., in PET tracers) will not only ensure a) good imaging quality due to its physical characteristics (low average positron energy), but also the possibility of delayed imaging, which is expected to improve diagnostic sensitivity and thus image contrast due to the washout of radioactivity from the background, b) a large distribution radius due to its relatively long half-life (t 1 / 2 61 Cu = 205.5 minutes), while c) still keeping the radiation burden on patients at the lowest level. A full description of a new process for producing high-purity 61 Cu (in the form of 61 Cu]CuCl2) is provided in this application, which can be used in radiopharmaceutical applications at high radioactive concentrations and high volumes, such as as a positron emitter in PET tracers. So far, the use of 61 Cu, especially high-purity 61 Cu in radiotracers has not been documented.

[0813] Trace metals and cold copper compete with 61 Cu for binding to chelating agents (e.g., NODAGA) in this order: cold Cu(II) (i.e., stable isotope) > Zn(II) > Fe(III) > Sn(IV) > Ti(IV) > Al(III.). The competition from these trace metals and cold copper significantly reduces the radiolabeling yield and radiochemical purity of the tracer, see Innovative ComplexatioNStrategies for the IntroductioNof Short-lived PET Isotopes into Radiopharmaceuticals(Page 105). Common sources of trace metals are the raw nickel metal powder itself, especially isotopically enriched nickel, any metals in the reagents and instruments used, such as iron. The purification process (ion exchange column) removes most of the trace metals except for cold metals (especially relevant are the stable isotopes 69 Cu and 65 Cu), which pass into the product fraction by being carried as the same element as the desired 61 Cu. One way to prevent cold copper contamination and related chemical purity degradation is to pass the dissolved nickel raw material (stable isotope) through the process and separate the cold copper from the nickel before plating (for ICP-MS analysis, see Figure 8 ), and Table 4 shows the chemical purity and resulting impurity distribution of nat Ni or 61 Ni bombarded with 61 Cu]CuCl2.

[0814] Table 4. Chemical purity of nat Ni relative to 61 Ni transmuted 61 Cu

[0815]

[0816] Radionuclide purity

[0817] Radionuclide purity is important in radiopharmacy because any radionuclide impurities increase the radiation dose received by the patient and may also degrade the quality of any imaging procedures performed. For example, if significant levels of other radionuclides are present, the biodistribution may be altered. Radionuclide samples contain some contaminants originating from the preparation process or the decay of the main radionuclide. Radionuclide impurities may occur as a result of the manufacturing process; for example, for nuclides produced by a cyclotron, there may be contaminants due to impurities in the target or the energy of the reaction. To control the impact of these contaminants on the radiation dose received by the patient, limits are set on the maximum allowable contamination levels. These limits are defined by government agencies, for example, in pharmacopoeial monographs, and vary depending on the physical decay characteristics of the relevant radionuclide and possible contaminants. After bombardment, high-resolution radionuclide purity measurements of the sample wells can be made using gamma-ray spectrometry. Then, the activity of the long-lived isotopes is extrapolated back to EoB or EoS or even expiration. The high activity emitted by long-lived radionuclide impurities greatly increases the cost and complexity of managing the disposal of all consumables in contact with the nuclide composition.

[0818] By deuteron irradiation of natural nickel and 60 Ni and 61Proton irradiation of Ni was used to prepare long-lived isotopes of cobalt: 56 Co, 57 Co, 58 Co and 60 Co. Other long-lived radionuclides (such as 110m Ag, 108m Ag and 109 Cd) are produced by irradiating a common silver backing material that is dissolved with the starting material during the purification process. Due to their long half-lives, the proportion of these radionuclides increases over time compared to 61 Cu, reducing the radionuclide purity of the product, especially at later time points when nat Ni is used as the starting material. Although most cobalt isotopes can be separated during the purification process, 110m Ag, 108m Ag and 109 Cd ultimately end up in the 61 Cu fraction and nickel solution, which are further used in the recycling of irradiated target coatings. Long-lived radionuclides become problematic when considering the radiation burden on patients and the accumulation of radioactive waste. Third-party target disk manufacturers do not disclose contamination from non-niobium target disk backings (e.g., silver). As provided by the present disclosure, for example, in view of the radionuclide purity and chemical purity of samples prepared after subatomic particle bombardment, separation, and purification, methods for preparing and using target disks containing niobium exhibit advantages. A detailed comparison of known 61 Cu products (prepared by prior art methods via Ag backings and plated targets) with 61 Cu as provided by the present disclosure is provided below.

[0819] Considering these factors, a niobium backing material was selected due to its inert nature towards acids at room temperature and at high temperatures. This property allows the niobium backing material to resist the acidic media used during the dissolution and purification processes. By doing so, higher radionuclide and chemical purities can be achieved in aqueous solutions of radioactive metals, ultimately leading to higher purity of radiopharmaceuticals prepared from the desired 61 Cu isotopes. Although there are methods for plating niobium, this element has not been used in radionuclide preparation due to poor adhesion of the plated Ni material (as discussed above). Ni (or 68 Ga used for preparing 68The Zn) requires sufficient adhesion to withstand the thermal load (1200 W) during irradiation and pneumatic shuttle acceleration of the target disk at pressures from 5 bar to 7 bar and during the sudden stop at the head. However, on the other hand, the plated Ni (or Zn) must dissolve sufficiently during the dissolution and purification process. Plasma-coated niobium backing was tried for plating nickel (Ni). However, this process led to loss of Ni from the niobium backing and incomplete dissolution. The thermal processes involved in plasma coating altered the grain structure of the niobium backing material, resulting in a strong bond between the plated nickel and niobium. This strong bond made it difficult for the nickel to dissolve completely, causing losses. The plasma coating process itself led to very high losses of the target coating, making the use of this process infeasible, especially in the case of very expensive highly enriched target metals. The main reference for this summary is the IAEA document on the production of radionuclides in cyclotrons, IAEA RADIOISOTOPES AND RADIOPHARMACEUTICALS, REPORTS, Issue 1. (INTERNATIONAL ATOMIC ENERGY AGENCY VIENNA, 2016) In addition, the monetary assessment of the acquisition cost of niobium used as a backing material shows a cost 40% lower compared to commonly used backing materials such as gold, silver, and platinum, where the cost is in the range of €80 to €120 / backing material (single target disk).

[0820] Meanwhile, elements related to the radiochemical purity of the labeling process can be controlled by manufacturing the plating solution under the controlled conditions described in this application. By obtaining the plating solution from a raw material base material such as nickel, the possibility of contamination is now independent of external sources and suppliers. The materials and equipment used in these cases are inert glass beakers and falcon tubes (ensuring no unwanted substances are present), TraceSelect ultrapure water, pure reagents (trace metal grade), inert target disk adapters, and electrolytic cells (on the electroplating unit), etc. In this way, contaminants of trace metals can all be minimized, reduced, or avoided together. This difference between 99.9% purity and 99.99% purity plays a role in the resulting chemical purity of the radionuclide and thus in the radiochemical purity of the radiopharmaceutical prepared from the radionuclide, where the presence of cold Cu, Zn, Fe, Sn, Ti, or Al or any of their salts is a problem because they will compete with the desired radionuclide ( 61 Cu) for binding to the chelating agent in the tracer.

[0821] The robustness of the plating is tested by drop and scratch tests. This assessment ensures that the electrodeposited substrate on the backing will withstand the mechanical shock of the shuttle system and establishes an increased probability of survival under the cyclotron beam.

[0822] In certain embodiments, on a GE PET Trace cyclotron using an ARTMS or a GE shuttle system, the target disk is irradiated with 8.4 MeV deuterons in the range of 40 μA to 45 μA or with 13.2 MeV deuterons at 40 μA to 45 μA for an average duration of 120 minutes.

[0823] In certain embodiments, on a GE PET Trace cyclotron using an ARTMS or a GE shuttle system, the target disk is irradiated with 8.4 MeV deuterons in the range of 40 μA to 45 μA or with 13 MeV protons at 10 μA to 100 μA for an average duration of 120 minutes.

[0824] Dissolution of Ni from the niobium backing is effected via a dissolution system in 10 M HCl. Subsequently 61 Cu is purified in a FASTlab synthesis unit with two subsequent ion exchange resins. The processing time for these purifications can be up to 60 minutes.

[0825] The resulting 61 Cu]CuCl2 solution has an average activity of 1.7–4.5 GBq. This activity is measured using a dose calibrator and its radionuclide purity is measured by a calibrated gamma spectrometer, e.g., at PSI in Switzerland.

[0826] Gamma spectrometry measurements were performed to identify any radionuclide impurities, especially long-lived radionuclides. These results show that for the niobium backing material when using the method disclosed in the present application, the nat Ni and 61 impurities of Ni are reduced by 89.3% and 94% relative to a silver backing material. ICP-MS measurements were performed on the cold dissolution product by Labor Veritas in Switzerland to monitor the elemental impurities present in the product according to ICH-Q3D. All detected impurities are within the specified ICH-Q3D concentrations (see ICH-Q3D Guidelines, page 25).

[0827] Using the same plating parameters as described above also enables plating of highly enriched 61 Ni, to achieve higher yields and industrial production using proton irradiation (typically at 10 μA to 100 μA, 13 MeV proton irradiation for 20 minutes to 2 hours and up to 61 one half-life of Cu).

[0828] After the irradiated target disk is automatically transferred from the cyclotron to the hot cell docking station, the capsule is transferred to the QIS dissolution unit using forceps. The transmuted target metal is dissolved from the niobium backing material using 1:1 7M HCl:30% H2O2 (ultratrace analysis, Merck) (4 mL). The acid-peroxide mixture is circulated and the target disk and target metal surfaces are immersed to dissolve all irradiated elements at approximately 60 °C at 2 mL / min for approximately 23 minutes. When the target metal is completely dissolved, the acidic solution containing the dissolved metal is drained and the QIS system is rinsed with 10M HCl (3 mL). The combined acidic solution is then fed forward to the FASTlab purification unit.

[0829] New 61 Cu radiotracer

[0830] Radiotracers containing PSMA-I&T, SS (somatostatin) analogs, and FAP inhibitors in combination with 61 Cu have not been reported. Therefore, the NODAGA-PSMA-I&T, NODAGA-LM3, NODAGA-F1, NODAGA-F2, NODAGA-F3, and NODAGA-F4 discussed in this application are new precursors or intermediates. Similarly, the radiotracers 61 61 Cu]Cu-NODAGA-LM3, 61 61 Cu]Cu-NODAGA-F1, 61 61 Cu]Cu-NODAGA-F2, 61

[0831] 61

[0832] In recent years, radiotracers targeting prostate-specific membrane antigen (PSMA) have had an impact on the imaging and treatment of prostate cancer. 68 Ga-labeled urea-based PSMA inhibitors are the most commonly used radiotracers in this disease entity. 18 ​​​​​​F-labeled derivatives have emerged as an alternative, mainly to meet the growing demand for PSMA-targeted PET imaging. However, this comes at the cost of the possibility of facile chelator-based kit radiolabeling and a therapeutic companion (theranostic); radioactive metals are possible options. As an alternative, in certain embodiments, cyclotron-produced 61 Cu (Eβ + average = 500 keV, Eβ + maximum = 1216 keV, t 1 / 2 = 3.34 h), which combines the favorable logistics of 18 F, chelator-based radiochemistry, and other therapeutic options (e.g., 67 Cu). Here, the initial preclinical data on 61 Cu]Cu-NODAGA-PSMA-I&T radiotracer are reported.

[0833] 61 Cu]CuCl2 was prepared from irradiated Ni targets on the cyclotron at the University Hospital Zurich and then subjected to cassette-based automated separation (1) as previously described. DOTAGA-(I-y)fk(Sub-KuE)(PSMA-I&T, DOTAGA-PSMA-I&T in this application) (2) and NODAGA-(I-y)fk(Sub-KuE)(NODAGA-PSMA-I&T) were labeled with 61 Cu]CuCl2 in ammonium acetate buffer at pH 8 at room temperature (95 °C for the DOTAGA chelator). Both 61 Cu]Cu-PSMA radiotracers were evaluated head-to-head in vitro using LNCaP cells and in LNCaP xenograft nude mice by dynamic and static PET / CT imaging and biodistribution studies.

[0834] 61 Cu]Cu-NODAGA-PSMA-I&T and 61 Cu]Cu-DOTAGA-PSMA-I&T were prepared, both with a molar activity of 24 MBq / nmol and without purification after preparation. 61 Cu]Cu-NODAGA-PSMA-I&T is more hydrophilic than 61 Cu]Cu-DOTAGA-PSMA-I&T (logD of -2.95 ± 0.08 and -2.69 ± 0.44, respectively). In in vitro experiments, both radiotracers showed similar PSMA-mediated cellular uptake (about 35% after 2 h at 37 °C), with 50 - 60% internalized. 61 ​​Cu]Cu-NODAGA-PSMA-I&T and 61 PET / CT images of Cu]Cu-DOTAGA-PSMA-I&T showed significant differences. 61 Cu]Cu-NODAGA-PSMA-I&T accumulated in tumors, gradually increasing from 15 minutes to 60 minutes after injection, and also accumulated in the kidneys. The renal uptake could be reduced by adjusting the injection volume. 61 Cu]Cu-DOTAGA-PSMA-I&T showed 61 lower tumor uptake than Cu]Cu-NODAGA-PSMA-I&T, and also lower renal uptake, and showed high activity in the liver. The accumulation in the liver might be due to 61 the instability of the Cu]Cu-DOTAGA complex in vivo. A comprehensive biodistribution study of these two radiotracers in LNCaP xenograft tumors was provided.

[0835] Compared with the DOTAGA chelator, the NODAGA chelator was proven to be a perfect match for 61 Cu]Cu-based radiotracers. 61 Cu]Cu-NODAGA-PSMA-I&T exhibited 61 better characteristics than Cu]Cu-DOTAGA-PSMA-I&T, including but not limited to higher tumor uptake and lower background activity, which might be attributed to its higher in vivo stability. Therefore, 61 Cu]Cu-NODAGA-PSMA-I&T is a potential candidate for 61 clinical translation of Cu]Cu-based PSMA-targeted PET imaging.

[0836] 61 Cu]Cu-PSMA-I&T and 68 Ga]Ga-PSMA-I&T

[0837] Comparison for prostate cancer PET imaging

[0838] Targeting prostate-specific membrane antigen (PSMA) is a highly relevant target, highly relevant to the detection and treatment (theranostics) of prostate cancer. For this purpose, many low molecular weight PSMA inhibitors have been developed, among which 68 Ga]Ga-PSMA-11 was recently approved. Other inhibitors, such as 68 Ga]Ga-PSMA-617 and 68 Ga]Ga-PSMA-I&T, when used with 177 ​The use of Lu enables the provision of theranostic agents. Given the growing clinical needs, the production capacity of the 68 Ga tracers (2 - 3 patient doses) produced by the generator has raised some concerns. A valuable alternative is 61 Cu (Eβ 68 The production capacity of 68 Ga tracers (2 - 3 patient doses) produced by the generator has raised some concerns. A valuable alternative is 61 Cu (Eβ + average value = 500 keV, Eβ + maximum value = 1216 keV, t 1 / 2 = 3.34 hours). 61 61 Cu can be produced on a large scale in a cyclotron. At the same time, compared with 68 Ga, its lower energy and longer half-life (enabling delayed imaging) can produce finer imaging quality. In addition, 68 compared with 68 Ga, its lower energy and longer half-life (enabling delayed imaging) can produce finer imaging quality. In addition, 61 61 Cu also has a therapeutic companion 67 67 Cu. Based on the PSMA-I&T system, the comparison between 61 61 [ 61 Cu] 61 Cu-PSMA and 68 68 [ 68 Ga] 68 Ga-PSMA is reported in this application.

[0839] Since the 61 Cu-NODAGA complex is stable in vivo compared with 61 Cu-DOTAGA, the chelator DOTAGA on PSMA-I&T (referred to as DOTAGA-PSMA--I&T in this application) is replaced with NODAGA for 61 61 Cu labeling. 61 61 [ 61 Cu] 61 CuCl2 was produced by irradiating a Ni target on the cyclotron of the University Hospital of Zurich, and then subject to cassette-based automated separation as previously described (1). In terms of lipophilicity, in vitro cellular uptake in LNCaP cells, PET / CT imaging and quantitative biodistribution in nude mice bearing LNCaP xenografts, a head-to-head evaluation was performed on 61 61 [ 61 Cu] 61 Cu-NODAGA-PSMA-I&T and 68 68 [ 68 Ga] 68 Ga-DOTAGA-PSMA-I&T. Results: These two radiotracers were prepared, and their molar activities were both 24 - 30 MBq / nmol. Compared with 68 68 [ 68 Ga] 68 Ga-DOTAGA-PSMA-I&T, 61 61 [ 61 Cu] 61 Cu-NODAGA-PSMA-I&T showed higher hydrophilicity (logD = -2.95 ± 0.08 and -2.79 ± 0.41 respectively) and higher in vitro cellular uptake (26.6 ± 0.9% after 1 hour at 37°C, 12 ± 1.9% internalized, compared with cellular uptake of 20.6 ± 2.3% and internalized fraction of 9.8 ± 1.3% respectively). PET / CT images 1 hour after injection showed that the biodistribution patterns of these two radiotracers were the same, characterized by mainly accumulating in tumors - 61Cu]Cu-NODAGA-PSMA-I&T showed higher uptake - and accumulation in the kidneys. At 4 hours after injection 61 The biodistribution pattern of Cu]Cu-NODAGA-PSMA-I&T was the same on PET / CT images. By increasing the injection volume (200 to 400 to 1000 pmol), the 61 kidney uptake of Cu]Cu-NODAGA-PSMA-I&T could be significantly reduced, decreasing from 96% to 72% to 34% IA / g at 1 hour after injection. Conclusion: In terms of whole-body distribution, 61 Cu]Cu-NODAGA-PSMA-I&T was comparable to 68 Ga]Ga-DOTAGA-PSMA-I&T on PET / CT images, while showing higher tumor uptake and offering the possibility of delayed imaging. Compared with the established 68 Ga]Ga-PSMA tracers, 61 Cu]Cu-NODAGA-PSMA-I&T was considered for clinical evaluation. References: 1. J. Svedjehed et al., EJNMMI Radiopharmacy and Chemistry 2020; 5:21.

[0840] Methods for manufacturing target disks for medical cyclotrons (particle accelerators), methods for producing high-purity radioactive copper compositions using such target disks; methods for preparing targeted chelator constructs and methods for preparing radiotracers using high-purity radioactive copper compositions are provided in this application. Also provided in this application are the in vitro and in vivo extensive characterizations of 61 Cu]Cu-NODAGA-PSMA-I&T, 61 Cu]Cu-NODAGA-TOC, 61 Cu]Cu-NODAGA-LM3, 61 Cu]Cu-NODAGA-F1, 61 Cu]Cu-NODAGA-F2, 61 Cu]Cu-NODAGA-F3, 61 Cu]Cu-NODAGA-F3, 61 Cu]Cu-NODAGA-F4 and 61 Cu]Cu-NODAGA-FAPI-46 constructs; including 61 a direct comparison of Cu]Cu-NODAGA-PSMA-I&T with the following radiotracers currently used in clinical practice: 68 Ga]Ga-PSMA-I&T, 68Ga]Ga-PSMA-11 and 18 F]F-PSMA-1007. (For the known structure of 18 F]F-PSMA-1007, see Katzschmann et al. Pharmaceuticals 14(3):188 in 2021) also provided 61 Cu]Cu-NODAGA-TOC and 61 Cu]Cu-NODAGA-LM3 and 68 Ga]Ga-DOTA-TOC (currently in clinical use) for direct comparison and process development of the radiotracers 61 Cu]Cu-NODAGA-PSMA-I&T and 61 Cu]Cu-NODAGA-LM3 for preparation of a Phase I clinical trial (ongoing).

[0841] 5.1. Example 1. High-purity 61 Cu]CuCl2

[0842] 5.1.1. Preparation of the plating solution

[0843] 5.1.1.1 Preparation of the buffer solution

[0844] Weigh ammonium chloride (4.6 g, Aldrich: 326372, Trace Select) into a clean (metal-free) Falcon tube (50 mL), and add a previously cleaned magnetic stir bar. Add 6 mL of TraceSelect water (Honeywell 95305) in one aliquot to rinse the walls of the Falcon to prevent any salt from sticking to the Falcon tube walls. Add 1 mL of 28% ammonium hydroxide (Sigma 338818) 8 times using a 1000 μL pipette with the corresponding pipette tip. Close the lid of the Falcon, and vortex the Falcon successively (1 - 2 minutes) (immersing it in an ultrasonic bath is a possible alternative, for 1 - 2 minutes) and shake until all the salt is dissolved. It is also possible to warm the Falcon tube (e.g., by rolling it between the hands) to increase solubility, temperature (e.g., about 23 °C, preferably between 23 °C - 25 °C). After the salt is completely dissolved, it is necessary to verify the pH acceptance criteria by measuring the pH of the solution at room temperature (e.g., with an electronic pH meter), with a pH range of 9.28–9.62. Seal the Falcon tube with paraffin film and store it at room temperature. Before use, redissolve any solid salt formation.

[0845] 5.1.1.2 Preparation of the nickel nitrate plating solution

[0846] Wash a 50 mL glass beaker with nitric acid (Trace Select), and then wash it with water (Trace Select). In a fume hood, dry the beaker by placing it on a hot plate set to 150 °C. Add 210 μg of natural (isotope distribution) nickel (powder, Sigma-Aldrich <50 μm, 99.7% trace metal basis, essentially free of any impurities except iron. The amount of copper impurity <0.3 ppm.) into the beaker, and add 4 mL of 65% nitric acid using a pipette. Place the beaker back on the active hot plate and set the stirring to 300 rpm. Ensure that the ventilation function of the fume hood is normal (release of NO2). During dissolution, the solution turns green. Reduce the solution to a volume of ≈600 μL by evaporation and remove it from the hot plate to cool to room temperature. Transfer the remaining solution to a 50 mL metal-free Falcon tube. Rinse the glass beaker in steps of 0.8 mL, 1 mL, and 1 mL with a total of 2.8 mL of Trace Select water, transferring each step to the Falcon tube before adding the next washing fraction. Add the buffer solution (4 mL), 11 mL of Trace Select water, and 3 mL of 28% ammonium hydroxide (Sigma 338818) to the Falcon tube. Measure the pH of the solution and adjust it to the desired pH by adding 28% ammonium hydroxide (Aldrich 338818) using a sterile B-Braun syringe.

[0847] 5.1.1.3 Preparation 60 Ni and 61 Examples of suitable starting materials for Ni and

[0848] The following are 60 Ni and 61 Example batches of Ni (as certified by American Isoflex in March 2018):

[0849] Table 5.

[0850]

[0851] Table 6.

[0852]

[0853] Table 7.

[0854]

[0855] Samples of natural nickel from Sigma-Aldrich are substantially free of any impurities other than iron. The amount of copper impurity is <0.3 ppm. See the Certificate of Analysis as described in Example 2. Other suitable sources of natural Ni include:

[0856] Nickel powder, <50 μm, 99.7% trace metal basis

[0857] Nickel rod, 6.35 mm in diameter, =99.99% trace metal basis

[0858] Nickel foil, 0.5 mm thick, 99.98% trace metal

[0859] 5.1.1.4 Preparation of Zinc Nitrate Plating Solution

[0860] Wash a 50 mL glass beaker with nitric acid (Trace Select), and then with water (Trace Select). In a fume hood, dry the beaker by placing it on a hot plate set to 150 °C. Weigh 210 μg of natural (isotope distribution) zinc (zinc powder, Sigma-Aldrich <10 μm, >98%) into the beaker, and add 4 mL of 65% nitric acid using a pipette. Place the beaker back on the hot plate and set the stirring to 300 rpm. Ensure that the ventilation function of the fume hood is normal (release of NO2). During dissolution, the solution turns green. Reduce the solution to a volume of ≈600 μL by evaporation and remove it from the hot plate to cool to room temperature. Transfer the remaining solution to a 50 mL metal-free Falcon tube. Rinse the glass beaker in steps of 0.8 mL, 1 mL, and 1 mL with a total of 2.8 mL of Trace Select water, transferring each step to the Falcon tube before adding the next wash fraction. Add 4 mL of buffer solution (prepared in Section 5.2.1.1), 11 mL of Trace Select water, and 3 mL of 28% ammonium hydroxide (Sigma 338818) to the Falcon tube. Measure the pH of the solution and adjust to the desired pH by adding 28% ammonium hydroxide (Aldrich 338818) using a sterile B-Braun syringe.

[0861] 5.1.2. Electroplating the Backing Surface

[0862] As described in this application, a disk-shaped niobium backing was obtained from high-purity Nb and cleaned with ethanol (high-purity) (28 mm × 1.0 mm), and inserted into a Comecer Electroplating Unit V21204. A platinum wire anode was placed such that the distance relative to the target disk surface was between approximately 1 and 3 mm, adjusted by a polymer spacer. The target disk mass was determined to be 5.25 grams. The niobium backing was (22 mm × 1.0 mm, weight 3.3 g). The plating solution was loaded into the electrolyte container and attached to the apparatus. The voltage was set to 4.5 V. After 5 min of stabilization, the current reading was 180 μA. The duty cycle of the pump was set to 45%. The plating solution changed from blue to transparent, and a slow decrease in current to 160 μA was observed over a 120-minute period. The plating process was stopped. The target disk was removed from the electrolytic cell and its weight was measured. The target disk also underwent microscopic evaluation, Figure 1 and 2 a DINOLite digital microscope was used to observe the crystal structure and uniformity of the surface. The target disk ( Figure 2 ) was stored in a metal-free Falcon tube under a nitrogen atmosphere.

[0863] 5.1.3. Results of Electroplating

[0864] After electroplating was completed, the target disk underwent microscopic evaluation, and a DINOLite digital microscope was used to observe the crystal structure and uniformity of the surface. As Figure 1 (subfigures A - C) can be seen, a uniform target coating with durable adhesion was obtained, also see Figure 2 .

[0865] 5.1.4. General Guidelines for the Preparation of High-Purity 61 Cu]Cl2

[0866] The purpose of this example was to enable the batch preparation of copper-61 ( 60 Cu) by deuteron irradiation of natural nickel and / or enriched 61 Ni. This effort was a proof of concept, and thus, there were no reference specifications for 61 Cu. However, we optimized the target performance, target geometry / material usage, irradiation parameters, and chemical processing methods to prepare 60 Cu]CuCl2 after scaling accordingly for enriched nat Ni irradiation or for 61 Ni irradiation. There were no pharmacopoeial specifications for radioactive copper, however, the test QC methods included evaluating the radionuclide purity and molar activity (to demonstrate the availability of the extracted 61 Cu]CuCl2).

[0867] This example contemplates the use of two different types of targets, natural nickel ( nat Ni) targets and highly enriched nickel-60 ( 60 Ni) targets, both of which are suitable for deuteron bombardment. However, nat Ni is inexpensive and available in high purity, while 60 Ni is still expensive and requires efficiency measures. If even higher yields are desired, the target preparation effort can be directly translated into a proton-based 61 Ni(p,n) 61 Cu pathway. However, considering the cost of enriched 61 Ni ($25 USD / μg approximately), this method requires target recycling.

[0868] The following set of guidelines enables the use of all types of targets in the preparation of 61 Cu, including high-purity 61 Cu]CuCl2 prepared by electroplating a Zn or Ni (any isotope enrichment) coating on a Nb target disk as provided in this application. Specific details of deuteron and proton irradiations are also provided. This protocol was followed to generate all 61 Cu compositions evaluated in the following examples.

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875] 5.1.5. 61 Purification and Characterization of

[0876] Via a dissolution chamber, the irradiated material of the solid target was dissolved in 6M HCl with a total volume of 7 mL with the addition of 30% hydrogen peroxide.

[0877] Using the cassette-based FASTlab platform, separation and purification were completed using TBP (tributyl phosphate-based) resin (1 mL) (particle size 50 - 100 μm; pre-packed, Triskem) and then weak basic (tertiary amine; TK201) resin (2 mL) (particle size 50 - 100 μm; pre-packed, Triskem), with each resin pre-conditioned with H2O (7 mL) and HCl (10 M, 7 mL). Cassette reagent vials were prepared using concentrated HCl (Optima Grade, Fischer Scientific), NaCl (ACS, Fischer Scientific), and milli-Q water (Millipore system, 18 MΩ-cm resistivity), 6 M HCl (2 x 4.2 mL), 5 M NaCl in 0.05 M HCl (4.2 mL). Then the subsequent 61 Cu was purified using two subsequent ion-exchange resins in the FASTlab synthesis unit.

[0878] 1) The acid-adjusted dissolution solution (approx. 7 mL) was loaded onto two columns in series and directed into the "Ni collection fraction". The TBP resin acts as a guard column as it retains Fe 3+ ions quantitatively, while Cu 2+ and Co 2+ complexes are retained quantitatively on the tertiary amine (TK201) resin.

[0879] 2) The two columns were washed with 6 M HCl (4 mL) to maximize Ni recovery for future recycling.

[0880] 3) The TK201 column was washed with 4.5 M HCl (5.5 mL) to elute most of the cobalt salts.

[0881] 4) The TK201 column was washed with 5 M NaCl in 0.05 M HCl (4 mL) to reduce the residual acid on the resin and further remove any residual cobalt salts.

[0882] 5) The TK201 column was washed with 0.05 M HCl (3 mL) to elute 61 Cu]CuCl2 quantitatively.

[0883] The resulting 61 Cu]CuCl2 solution of the plating material had an average activity of 1.0 - 4.5 GBq. The activity was measured using a dose calibrator from Comecer and its radionuclide purity was measured by a gamma spectrometer at PSI in Switzerland.

[0884] γ-spectrometry measurements were carried out to identify any radionuclide impurities, especially long-lived radionuclides. These results show that when using the method disclosed in the present application, the nat Ni and 61 Ni impurities on the niobium backing material are reduced by 89.3% and 94% relative to the silver backing material. ICP-MS measurements were carried out on the cold-dissolved product by Labor Veritas in Switzerland to monitor the elemental impurities present in the product according to ICH-Q3D. All detected impurities are within the specified ICH-Q3D concentrations (see ICH-Q3D Guidelines, page 25).

[0885] It is also possible to deposit highly enriched 61 Ni with the same plating parameters as described above, in order to achieve higher yields and industrial production using proton irradiation (typically at 80 μA to 100 μA, 13 MeV proton irradiation for 1 hour to 2 hours and up to 61 one half-life of

[0886] 5.1.6. Purity and activity evaluation of nat Ni(d,n) 61 Cu and 60 Ni(d,n) 61 Cu prepared using an Nb-backed target disk 61 Cu]CuCl2 composition.

[0887] This example provides information on the activity of the prepared 61 Cu generated using an Nb backing and the Ni electrodeposition target disk of the present disclosure; and cobalt radioisotopes, which were prepared by deuteron irradiation using a target disk containing a natural nickel target and a target disk containing enriched 60 Ni as the target (i.e., nat Ni(d,n) 61 Cu and 60 Ni(d,n) 61 Cu), respectively). The irradiated materials were dissolved and purified as described in Example 3.

[0888] The obtained and purified 61 Cu product and the waste generated during the deuteron irradiation of the purified natural nickel / Nb target disk and 60 Ni / Nb target disk were processed and analyzed by γ-spectrometry and are presented below.

[0889] The isotopic abundances using the natural nickel / Nb target disk and the enriched 60 Ni / Nb target disk were calculated based on the thick target yields of TENDL-2019.

[0890] 5.1.7. Radioactive Cobalt Content

[0891] Table 8 contains the activities of cobalt radioisotopes in different fractions after FASTlab purification, presented as the average of three measurements (N = 3 irradiations) using nat the Ni / Nb target disk. These activities were extrapolated to a 3 h and 50 μA beam at EoB (end of bombardment) + 2 h. The activity of 61 Cu]CuCl2 was experimentally determined in these irradiations and confirmed to be ~80% of the TENDL-2019-based estimate.

[0892] The activity of 61 Cu prepared by deuteron irradiation at 8.4 MeV, 50 μA for 3 h, and 80% efficiency (EoB + 2 h): 3052 MBq. For the variation of cobalt radioisotopes over time and the corresponding variation in 61 Cu purity, also see Figure 3 .

[0893] Table 8: Cobalt Isotopes: natNi / Nb Target Disk

[0894]

[0895]

[0896] Table 9 contains the calculated activities of cobalt radioisotopes obtained by using 99% enriched 60 Ni as the target metal. These activities were extrapolated to a 3 h and 50 μA beam at EoB (end of bombardment) + 2 h. The activity of 61 Cu was calculated accordingly.

[0897] The activity of 61 Cu prepared by deuteron irradiation at 8.4 MeV, 50 μA for 3 h, and 80% efficiency (EoB + 2 h): 11.552 MBq. For the variation of cobalt radioisotopes over time and the corresponding variation in 61 Cu purity, also see Figure 4 .

[0898] Table 9: Cobalt Isotopes: Enriched 60 Ni / Nb Target Disk.

[0899]

[0900] 5.1.7.1 Activity and Chemical Purity

[0901] Based on the activities (MBq) measured at different beam currents (μA) and time scales (5 - 60 minutes), it was found that using the method described in this application with nat Ni, 60Deuteron bombardment of Ni and 61 The measured activities from proton bombardment of Ni are about >80% of the theoretical activities calculated using the TENDL-19 cross-section database.

[0902] The activities of radioactive cobalt and other long-lived radionuclides were measured after release (more than 3 weeks after bombardment). Then the EOB activities of long-lived impurities were extrapolated.

[0903] In Table 10, the extrapolated radioactive cobalt radioactivity content and nat Cu]CuCl2 solution produced by deuteron irradiation of Ni as the target metal at 50 μA for 3 hours are given 61 along with the 61 Cu purity.

[0904] Table 10: Extrapolation of the 61 Cu activity and purity in the prepared [61Cu]CuCl2 solution from natural Ni / Nb target disks

[0905]

[0906]

[0907] Assuming a product expiration time of, for example, more than 3 weeks after EOB, there will be less than 0.03% of non-Cu radioactive isotopes ( 56 Co and 58 Co) left in the copper fraction. This value is below the allowable limit specified in the pharmacopoeia for Ga-68 cyclotron production (*0.1% at expiration for non-Ga radioactive isotopes):

[0908] Originating from nat Ni irradiation, 64 Cu (content ~5% at expiration) will be the main impurity, reducing the 61 radioisotope purity of the Figure 3 Cu product at longer irradiation times or storage periods (as shown by the gray curve in

[0909] In Table 11: 60 Ni / Nb target disks - after purification in FASTlab 61 Extrapolation of the Figure 4 Cu activity and purity. 61 The extrapolated radioactive cobalt activity content and 61 Cu purity of the prepared

[0910] Table 11: 60 Ni / Nb target disks - the prepared 61 Cu]CuCl2 solution in 61Extrapolation of Cu Activity and Purity.

[0911]

[0912]

[0913] Assume the expiration time of the product is 8 h after EoB, and there is less than 0.01% of non-Cu radioisotopes ( 56 Co and 58 Co) left in the Cu fraction. This value is one-tenth of the allowable limit specified in the pharmacopoeia (0.1%* at expiration for non-Ga radioisotopes) for 68 Ga produced by a cyclotron.

[0914] At the expiration time of 8 h after EoB, there is less than 0.02% of 64 Cu left in the copper fraction, which is one-hundredth of the specification required for 68 Ga (2% Ga radioisotopes are allowed for 68 Ga).

[0915] 5.1.8. Purity of 61 Cu]CuCl2 Prepared from Ni / Nb Target Disk: Comparison with Commercially Available Radionuclides

[0916] In Table 12, a comparison of the regulatory specifications for the purity of commercially available radionuclides is given, and the characteristics of high-purity 60 Ni / Nb and enriched 61 Ni / Nb target disks irradiated with deuterons (50 μA, 3 h) and prepared after purification in FASTlab are presented.

[0917] Table 12: Comparison between Commercially Available Radionuclides and nat Ni / Nb Target Disk and Enriched 60 Ni / Nb Target Disk-Irradiated 61 Cu]CuCl2 Solutions.

[0918]

[0919]

[0920] As the first notable comparison, prepared by a proton-irradiated cyclotron 68Ga also produces long-lived radionuclides (see, e.g., Applied RadiatioNand Isotopes, 65(10), 1101–1107, IAEA-TECDOC-1863 Gallium-68 CyclotroNProduction), especially from 66 Zn(p,pn) 65 Zn decay 65 Zn (half-life = 244 days). In enriched 68 Zn starting target metal, about 0.365% of 66 Zn, about 770 Bq of 65 Zn will be produced in a thick target by a 50 μA, 3 h beam with an energy of 13 MeV (based on TENDL-2019 calculations). Using natural Zn with an abundance of 27.7% of 66 Zn, 58 kBq of 65 Zn will be produced in one run of a 50 μA, 3 h beam. Therefore, the isotopic purity of Zn in the target metal is very important.

[0921] Similar to the preparation of 61 Cu]CuCl2, the preparation of 64 Cu]CuCl2 by proton irradiation of a cyclotron also produces long-lived cobalt radionuclides, namely, 55 Co, 57 Co, 58 Co, and 60 Co. (See, e.g., Nuclear Medicine&Biology, Vol. 24, pp. 35-43, 1997; Applied RadiatioNand Isotopes 68(2010)5–13) By operating with a degraded beam below 13 MeV, 60 Co (from 64 Ni(p,na) 60 Co) is reduced to 1 Bq per 50 μA, 3 h run. At beam energies below 13 MeV, 58 Ni(p,a) 55 Co formed by the 55 Co reaction will still be the main impurity (half-life = 17.53 hours). 170 Bq of long-lived 57 Co is mainly formed by 60 Ni(p,a) 57 Co at about 170 Bq under these conditions.

[0922] Note: These estimates use TENDL-2019 cross-section data and enriched 64The isotopic abundances of Ni were calculated from the thick target yields as follows: 0.00376% 58 Ni, 0.00298% 60 Ni, 0.0058% 61 Ni, 0.135% 62 Ni, 99.858% 64 Ni.

[0923] Example 1B. Enriched 61 Ni as the target metal on a target disk with a Nb backing

[0924] By 61 Proton bombardment of a Nb-backed target disk electroplated with Ni, via a cyclotron equipped with a solid target system, irradiated a high-purity niobium target disk coated with high-purity 61 Ni (purity 99.42%) to prepare 61 Cu. The proton beam current used was up to 100 μA and the beam energy was 13 MeV. An aluminum beam degrader was used.

[0925] In a heated dissolution chamber, in the presence of 30% H2O2, the material irradiated from the solid target was dissolved in 6 M HCl with a total volume of 7 mL. Via a GE Healthcare FASTlab 2 module, through a tributyl phosphate resin column and a weak ion exchange resin based on tertiary amine containing long-chain alcohol, 61 Cu was purified from metallic and radioactive metallic impurities. The product was finally eluted through a sterile filter Millex 4 mm Durapore PVDF 0.22 μm into a sterile vacuum vial in 3 mL of 0.05 M HCl in an ISO Class 5 environment. The vials were handled carefully using appropriate shielding and could be stored at room temperature until use, with appropriate shielding for transportation and handling.

[0926] Table 13. 61 Cu] Specifications of CuCl2.

[0927]

[0928]

[0929] * After release (≥ 3 weeks)

[0930] # Measured regularly

[0931] As shown in Table 14 and Figure 5 as shown, commercially available 61 Cu]CuCl2 contains radioactive nuclide impurities in addition to 110m Ag and 109 Cd, especially high levels of56 Co and 58 Co. By replacing silver with niobium as the backing material, Ag and Cd isotopes are eliminated from the Cu-61 product. For natNi, 56 the Co isotope is reduced by a factor of 9 and for Ni-61 by >2000-fold (requiring less radioactive waste shielding). A 50% reduction in long-lived cobalt isotopes was also observed (early final disposal of the waste generated). It is clear from the following data that the 61 radionuclide purity of the 61 Cu]CuCl2 produced by the method of the present disclosure is shown to be superior to previously known methods and products. High levels of long-lived Co, Ag, and Cd radionuclides impose a radiation burden on patients and pose radioactive waste problems for the consumables that come into contact with the

[0932] Table 14. The detailed radionuclide impurities present in commercially available 61 Cu]Cl2 compared to the high-purity 61 Cu of the present disclosure, expressed in Bq / g.

[0933]

[0934] The total radionuclide impurity characteristics are summarized and shown in Table 15 below and Figure 6 in which it is shown that the radionuclide impurities are reduced by 83%. When these impurities are present in the 61 Cu]CuCl2 product, they impose a radiation burden on patients, create waste problems, and reduce the quality of radiopharmaceuticals. They also interfere with the chelation process by competing with 61 Cu, which affects the radioactive labeling accuracy of the tracer. After changing the backing material from silver to the niobium backing provided in this application and using the nickel plating method described in this application, an 89.3% reduction in impurities was observed.

[0935] An additional 46% reduction was observed when Ni-61 was used as the starting material.

[0936] Table 15. Comparison of the total amount of radionuclide impurities in 61 Cu]CuCl2 from commercially available target irradiations with the impurities (expressed in Bq / g) generated by the target of the present disclosure.

[0937]

[0938] Due to the purity of 61 Cu at EoB and EoS (EoB + 2), the long-lived radionuclide impurities decay more slowly and thus, on a longer time scale, relative to 61The impurity profile can therefore vary greatly based on the isotopic abundance, purity, method, and process of producing the target disk, which affects [ 61 Type and content of radioactive nuclide impurities in finished Cu]CuCl2 products.

[0939] Figure 7 The results were compared with those prepared by using natNi target metal on commercial silver backing. 61 The radionuclide purity of the Cu]CuCl2 solution is comparable to that of the [ 61 The radionuclidic purity of the Cu]CuCl2 solution, when assessed by gamma spectroscopy at t=0 h and t=12 h, is given in Bq / g (total amount of radionuclidic impurities). The data presented highlight the [ 61 The excellent quality of Cu]CuCl2 solution, in which the purity after 12 hours is still far higher than the purity limit specified by the pharmacopoeia for similar medical radionuclides.

[0940] Table 16. [ 61 Cu]CuCl2 and [ 61 The radionuclide purity of Cu]CuCl2 is as measured at EOS and EOS+12 hours, which is comparable to the high purity [ 61 Cu]CuCl2 compared to commercially available 61 Radionuclide purity of Cu.

[0941]

[0942] 5.1.9. Endotoxin determination by Limulus amebocyte lysate (LAL test)

[0943] Using Charles River Endosafe TM -PTS system measures bacterial endotoxins by LAL test.

[0944] exist[ 61 During the dispensing of the Cu]CuCl2 solution, 1 mL aliquots were dispensed for quality control testing. These tests were performed in an unclassified quality control laboratory. The solution consisted of [ 61 Cu]CuCl2, 0.05M HCl (aqueous solution).

[0945] Table 17: LAL-tested [ 61 Cu]CuCl2 solution

[0946]

[0947]

[0948] Before analysis, the 61 Cu]CuCl2 solution (pH 1.3) was diluted using LAL reagent water and buffer to achieve a pH value in the range of 6 - 7.6. To adjust the pH, TRIS buffer was added to the 61 Cu]CuCl2 solution.

[0949] The following reagents were mixed in an endotoxin - free dilution tube to prepare the 61 Cu]CuCl2 dilution to be tested: dilution factor (1:75); 61 Cu]CuCl2 sample (10 μL); TRIS buffer (40 μL); water (700 μL). The mixing continued for about 30 seconds.

[0950] 5.1.10. Conclusion

[0951] Calculated from the TENDL - 2019 cross - section data, the experimental activity of 61 Cu prepared after deuteron irradiation was about 80% of the theoretical yield.

[0952] From 61 Cu, the main long - lived radionuclides in the radioactive waste fraction produced by the cyclotron are 56 Co, 57 Co, 58 Co, and 60 Co radioactive cobalt substances. After four years, it was calculated that 56 Co, 57 Co, and 58 Co had decayed to below the regulatory clearance limit LL*, leaving only 60 Co. *The clearance limit (LL) means the value corresponding to the radioactive concentration level of the material, below which the handling of the material is no longer subject to mandatory licensing or supervision).

[0953] To increase the 61 Cu]CuCl2 product yield and purity, target disks with 99% enriched 60 Ni or 61 Ni can be used. Using these targets, 61 Cu]CuCl2 extrapolated purity will be higher because 64 Cu will not form as radioactive isotope impurities. In addition, 56 Co and 60 Co content will be reduced by 100 times. On the other hand, 57 Co amount will quadruple (but at low activity), and58 The Co amount will double (but will decay below LL before 56 Co / 58 Co).

[0954] Preparation of Example 2 A-NODAGA-PSMA-I&T

[0955] General analytical reversed-phase high-performance liquid chromatography (RP-HPLC) was performed on a Nucleosil 100 C18 (5 μm, 125 × 4.0 mm) column (CS GmbH, Langerwehe, Germany) using a Sykam gradient HPLC system (Sykam GmbH, Eresing, Germany). Peptides were eluted at a constant flow rate of 1 mL / min using different gradients of 0.1% (v / v) aqueous trifluoroacetic acid (TFA) solution (solvent A) and 0.1% TFA (v / v) acetonitrile solution (solvent B) (specific gradients are cited in the text). UV detection was performed at 220 nm using a 206 PHD UV-Vis detector (Linear TM Instruments Corporation, Reno, USA). Retention times tR and capacity factors K' are cited in the text. Preparative RP-HPLC was performed on the same HPLC system using a Multospher 100 RP 18-5 (250 × 20 mm) column (CS GmbH, Langerwehe, Germany) at a constant flow rate of 9 mL / min. Radio-HPLC of the radioiodinated reference ligand was performed using a Nucleosil 100 C18 (5 μm, 125 × 4.0 mm) column.

[0956] Synthesis of carboxy-protected Lys-urea-Glu core (KuE)

[0957]

[0958] Step a. 2-(1H-imidazole-1-carboxamido) glutaric acid (S)-di-tert-butyl ester (1) was synthesized from glutamic acid di-tert-butyl ester. In the presence of triethylamine (TEA), under anhydrous conditions, it was reacted with carbonyldiimidazole (CDI) to form an intermediate acyl imidazole derivative. HPLC (10% to 90% B in 15 minutes): tR = 12.2 minutes; K′ = 5.78. Calculated monoisotopic mass of compound 1 (C 17 H 27 N3O5): 353.4; found: m / z = 376.0 [M+Na]+.

[0959]

[0960] Step b. Cbz-(OtBu)KuE(OtBu)2 (2): A solution of 3.40 g (9.64 mmol, 1.0 eq) of Compound 1 in 45 mL of 1,2-dichloroethane (DCE) was cooled to 0 °C, and 2.69 mL (19.28 mmol, 2.0 eq) of triethylamine (TEA) and 3.59 g (9.64 mmol, 1.0 eq) of Cbz-Lys-OtBu HCl were added under vigorous stirring. The reaction mixture was heated to 40 °C overnight. The solvent was removed in vacuo, and the crude product was purified by flash chromatography on silica gel, using an ethyl acetate / hexane / TEA (500 / 500 / 0.8 (v / v / v)) eluent mixture. After evaporation of the solvent, 4.80 g of Compound 2 as a colorless viscous oil was obtained (yield: 80%, based on L-glutamic acid di-tert-butyl ester hydrochloride). HPLC (40% to 100% B in 15 minutes): tR = 14.3 minutes; K′ = 8.53. The monoisotopic mass of Compound 2 (C 32 H 51 N3O9) was calculated to be 621.8; found: m / z = 622.2 [M+H]+, 644.3 [M+Na]+.

[0961]

[0962] Step c. (OtBu)KuE(OtBu)2 (3): For Cbz deprotection, 6.037 g (9.71 mmol, 1.0 equiv) of Compound 2 was dissolved in 150 mL of ethanol (EtOH), and 0.6 g (1.0 mmol, 0.1 equiv) of palladium on activated carbon (10%) was added. After purging the flask with hydrogen, the solution was stirred overnight under a slight hydrogen pressure (balloon). The crude product was filtered through diatomaceous earth, and the solvent was evaporated in vacuo to give the desired product as a waxy solid (4.33 g, yield 91.5%). HPLC (10% to 90% B in 15 minutes): tR = 12.6 minutes; K′ = 6.41. The monoisotopic mass of Compound 3 (C 24 H 45 N3O7) was calculated to be 487.6; found: m / z = 488.3 [M+H]+, 510.3 [M+Na]+.

[0963] Synthesis of the Protected Sub-KuE Conjugate

[0964]

[0965] NHS-Sub-(OtBu)KuE(OtBu)2 (4): Dissolve compound 3 (40 μg, 0.08 mmol, 1 eq) in 500 μL of N,N-dimethylformamide (DMF), and add 57 μL (0.41 mmol, 5 eq) of TEA. Add this solution dropwise (within 30 minutes) to a solution of 33.2 μg (0.09 mmol, 1.1 eq) of disuccinimidyl suberate (DSS). After stirring for an additional 2 hours at room temperature (RT), concentrate the reaction mixture in vacuo, dilute with ethyl acetate, and extract with water (twice). Dry the organic phase over Na2SO4, filter, and evaporate to dryness. Since the crude compound 4 had sufficient purity, it was used in the next reaction without further purification. HPLC (10% to 90% B in 15 minutes): tR = 16.9 minutes; K′ = 8.39. Calculated monoisotopic mass of compound 4 (C 36 H 60 N4O 12 ): 740.4; found: m / z = 741.2 [M+H]+, 763.4 [M+Na]+.

[0966] Synthesis of the peptide linker

[0967]

[0968] Fmoc-3-iodo-D-Tyr-D-Phe-D-Lys(Boc) (Fmoc-(I-y)fk): Dissolve Fmoc-Lys(Boc)-OH (1.5 equiv) in anhydrous dichloromethane (DCM), and add N,N-diisopropylethylamine (DIPEA) (1.25 equiv). Suspend the dry TCP resin and stir at room temperature for 5 minutes. Add 2.5 equiv of DIPEA and continue stirring for 90 minutes. Then, add 1 mL of methanol (MeOH) per gram of resin to cap unreacted trityl chloride groups. After 15 minutes, filter out the resin, wash it twice with DCM, DMF, and MeOH, respectively, and then dry in vacuo. Calculate the final loading of resin-bound Fmoc-Lys(Boc)-OH based on the weight difference.

[0969] Assembly of the peptide sequence H2N-3-iodo-D-Tyr-D-Phe- onto resin-bound Lys(Boc) was carried out according to the standard Fmoc protocol using 1.5 equiv of 1-hydroxybenzotriazole (HOBt) and O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) as the coupling agent and 4.5 equiv of DIPEA. After coupling the last amino acid, wash, dry, and store the resin in a desiccator until further functionalization.

[0970] Coupling of the Chelating Moiety

[0971]

[0972] Pre-swell the Fmoc-3-iodo-D-Tyr-D-Phe-D-Lys(Boc)-TCP resin in N-methylpyrrolidone (NMP) for 30 minutes. After cleaving the N-terminal Fmoc protecting group with 20% piperidine (v / v) in DMF, wash the resin 8 times with NMP.

[0973] NODAGA-iodo-D-tyrosine-D-phenylalanine-D-lysine (NODAGA-(I-y)fk,5): For 38 μmol of resin-bound peptide, add a solution of 31 μg of NODAGA-tritert-butyl ester (57 μmol, 1.5 eq), 108 μg of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 0.28 μmol, 5 eq) and 87 μL of DIPEA (570 μmol, 15 eq) in NMP to the resin. After shaking for 72 hours, wash the resin with NMP and DCM. HPLC (10% to 90% B in 15 minutes): tR = 8.2 minutes; K′ = 4.13. Calculated monoisotopic mass of compound 5 (C 39 H 54 IN7O 12 ) : 939.29;

[0974] Perform resin cleavage (2 × 30 minutes) and simultaneous tert-butyl deprotection using a mixture of 95% TFA, 2.5% triisobutylsilane (TIBS), and 2.5% water (v / v / v). Then concentrate the combined product solution, precipitate the crude peptide with diethyl ether, and dry it in vacuo. Since the crude product had sufficient purity, it was used in the subsequent reaction steps without further purification.

[0975] Condensation of the Chelator-Conjugated Peptide and the PSMA Binding Motif

[0976]

[0977] NODAGA-(I-y)fk(Sub-KuE)(6): Dissolve compound 5 (15 μg, 18 μmol, 1 eq) and TEA (13 μL, 90 μmol, 5 eq) in 600 μL of DMF, and slowly add compound 4 (18 μmol, 1 eq) dissolved in 400 μL of DMF. After stirring at room temperature for 2 hours, evaporate the reaction mixture to dryness. Subsequently, dissolve the crude product in TFA and stir for 40 minutes to remove the tBu protecting group. After precipitation in diethyl ether, dissolve the crude product in water and purify it by preparative RP-HPLC (25% to 40% B in 20 minutes). HPLC (10% to 90% B in 15 minutes): tR = 10.3 minutes; K′ = 5.44. Compound 10 (C 59 H 85 IN 10 O 21 ) monoisotopic mass calculated value: 1396.5. Regarding 1 H-NMR spectrum and related chemical shifts, see Figure 32A -C.

[0978] Alternatively, perform HPLC analysis using a Waters XBridge Peptide BEH C18, 250×4.6 mm, 3.5 μm column; eluent A: water (0.1% H3PO 4) ; eluent B: acetonitrile (0.1% H3PO4); at a flow rate of 1 mL / min, linearly increase from 10% B to 90% in 15 minutes; detect at 215 nm; retention time is 12.4 minutes. MALDI-TOF calculated value [MH] + 1397.5 m / z. Measured value is 1397.8 m / z. This analysis is performed in linear positive ion mode with cyano-hydroxycinnamic acid as the matrix.

[0979] Example 2 - Complexation of native copper ( nat Cu) with NODAGA-targeted chelator constructs of PSMA ligand, somatostatin analog, and FAP ligand, DOTAGA-targeted chelator constructs, and DOTA-targeted chelator constructs

[0980] By combining each targeted chelator construct with 1.5-fold excess of natCuCl2×2H2O was incubated in ammonium acetate buffer (0.5 M, pH 8) at 95 °C for 15 minutes (for NODAGA-conjugates, NODAGA-PSMA-I&T, NODAGA-TOC, NODAGA-LM3, NODAGA-F1, NODAGA-F2, NODAGA-F3, NODAGA-F4, and NODAGA-FAPI-46) or 30 minutes (for DOTAGA-conjugates and DOTA-conjugates, DOTAGA-PSMA-I&T and DOTA-TOC) to prepare nat Cu complexes. Uncomplexed nat Cu ions were removed by SepPak C-18 purification. nat The Cu complexes were eluted with methanol, evaporated to dryness, redissolved in water, and lyophilized. The purity of all complexes was confirmed by liquid chromatography and mass spectrometry (LC-MS). Table 13 presents the retention time (tR) compared to the theoretical mass and the mass of the resulting ion [M+2H] 2+ (mass-to-charge ratio, m / z), confirming the identity of the nat Cu-complexed conjugates formed.

[0981] Table 13. nat Analytical data of Cu conjugates. The analysis was performed using a liquid chromatography–mass spectrometry (Shimadzu LC2020) system with a Waters XBridge C18 5 μm, 150 x 4.6 mm column and a gradient of 15–65% acetonitrile (0.1% TFA) / water (0.1% TFA) in 15 minutes at a flow rate of 2 mL / min. For F1, F2, F3, and F4, the analysis was performed using a liquid chromatography–mass spectrometry (Shimadzu LC2020) system with a Gemini C6 Phenyl 5 μm, 250 x 4.6 mm column and a gradient of 15–80% acetonitrile (0.1% TFA) / water (0.1% TFA) in 15 minutes at a flow rate of 2 mL / min.

[0982] Table 13: nat Analysis of Cu-complexed targeting conjugates

[0983]

[0984]

[0985] m / z = mass-to-charge ratio of the ion [M +2 + H] 2+ ; tR = retention time

[0986] Example 3 - NODAGA-radiotracers, DOTAGA-radiotracers and DOTA-radiotracers of PSMA ligands and somatostatin analogs as well as FAPI inhibitors 61 Cu labeling

[0987] Dilute an aliquot of the NODAGA targeting chelator construct, DOTAGA targeting chelator construct or DOTA targeting chelator construct (3 - 6 nmol, 1 μg / mL in water) in 0.25 - 0.30 mL of ammonium acetate (or sodium acetate) (0.5 M, pH 8), and then add 0.1 - 0.7 mL 61 0.05 M HCl solution of

[0988] 61 Cu]CuCl2 (70 - 240 MBq). Depending on the chelator, incubate the reaction mixture for 15 minutes at different temperatures; incubate the NODAGA constructs (NODAGA - PSMA - I&T, NODAGA - TOC, NODAGA - LM3, NODAGA - F1, NODAGA - F2, NODAGA - F3, NODAGA - F4 and NODAGA - FAPI - 46) at room temperature (about 20 - 25 °C), while incubate the DOTAGA constructs and DOTA constructs (DOTAGA - PSMA - I&T and DOTA - TOC) at 95 °C. The reaction pH is between 5 and 6.

[0989] During the dispensing of 61 Cu]Cu - NODAGA PSMA - I&T solution, take 1 mL aliquots for quality control testing. The testing is carried out in a non - graded quality control laboratory.

[0990] The solution consists of 61 Cu]Cu - NODAGA PSMA - I&T, 0.05 M HCl, 0.5 M sodium acetate (containing 20 μg / mL ascorbic acid) and 0.9% NaCl sterile injection solution.

[0991] Table 14 (quality parameters for pre - release (or distribution) testing of physical products) and Table 15 (quality parameters for post - release testing) list the 61 specifications and testing methods of

[0992] Table 14. Specifications of 61 Cu]Cu - NODAGA - PSMA - I&T solution for pre - release testing

[0993] ​

[0994] Table 15. After release test 61 Specification of Cu]Cu-NODAGA-PSMA-I&T solution

[0995]

[0996] Protocol 1. 61 Cu-labeling reactions of NODAGA-PSMA-I&T, NODAGA-TOC, NODAGA-LM3, NODAGA-F1, NODAGA-F3, NODAGA-F2 and NODAGA-F4

[0997]

[0998]

[0999]

[1000] Quality control was performed by reversed-phase high-performance liquid chromatography (RP-HPLC) (radio-HPLC) connected to a radioactive detector. The results of radio-HPLC are provided in Table 16 below.

[1001] At a molar activity of 24 MBq / nmol, 61 Cu]Cu-DOTAGA-PSMA-I&T and 61 Cu]Cu-NODAGA-PSMA-I&T were prepared without post-labeling purification.

[1002] Table 16: 61 Radiochemical purity and retention time (tR) of Cu radiotracers, using a standard HPLC method with an increasing gradient concentration of aqueous acetonitrile containing formic acid (Shimadzu LC-20A Prominence HPLC system) equipped with a radio-HPLC flow monitor (Elysia-Raytest Gabi Star) column (125.4.6 Nucleosil 100-5-C18 AB).

[1003] Radiotracer Radiochemical purity tR (minutes) <![CDATA 61 Cu]Cu-DOTAGA-PSMA-I&T]]> ≥97％ 7.2±0.2 <![CDATA 61 Cu]Cu-NODAGA-PSMA-I&T]]> ≥98％ 7.1±0.2 <![CDATA 61 Cu]Cu-DOTA-TOC]]> ≥98％ 9.8±0.2 <![CDATA 61 Cu]Cu-NODAGA-TOC]]> ≥98％ 10.2±0.2 <![CDATA 61 Cu]Cu-NODAGA-LM3]]> ≥98％ 10.7±0.2 <![CDATA 61 Cu]Cu-NODAGA-F1]]> ≥98％ 5.9±0.2 <![CDATA 61 Cu]Cu-NODAGA-F3]]> ≥97％ 6.1±0.2 <![CDATA 61 Cu]Cu-NODAGA-F2]]> ≥98％ 6.1±0.2 <![CDATA 61 Cu]Cu-NODAGA-F4]]> ≥98％ 6.4±0.2 <![CDATA 61 Cu–NODAGA-FAPI-46]]> ≥95％ 5.7±0.2

[1004] All constructs were labeled with 61 Cu with extremely high yields and purities. Uncomplexed 61 Cu was removed from the reaction mixture without further purification steps, allowing the direct use of the formed radiotracer.

[1005] Example 4 -61 The lipophilicity of Cu-labeled NODAGA radiotracers, DOTAGA radiotracers and DOTA radiotracers and their 68 comparison with their Ga counterparts and reference radiotracers

[1006] The lipophilicity / hydrophilicity of the radiotracers was evaluated by determining the partition coefficient (D) between the aqueous and organic phases (expressed as log D (pH = 7.4)) according to the “shake-flask” method. The radiotracer (1 μM) was added to a 50:50 pre-saturated mixture of 1-octanol and phosphate buffer solution (PBS pH 7.4). The solution was vortexed for 30 minutes and then centrifuged at 3,000 rpm to achieve phase separation. Aliquots of each phase were collected and measured in a gamma counter. The partition coefficient was calculated as the mean of the logarithms of the ratios of the radioactivity in the organic phase and PBS phase. The results are summarized in Table 17.

[1007] Table 17. 61 The lipophilicity of Cu radiotracers and 68 Ga radiotracers (reference radiotracers), expressed as the logarithmic partition coefficient D (log D (octanol / PBS pH 7.4)). The results are the mean ± standard deviation of at least two independent experiments (in triplicate each).

[1008] Table 17: Lipophilicity of radiotracers

[1009]

[1010]

[1011] * 68 Ga]Ga-PSMA-11 is known and is disclosed in Carlucci et al., J. Nucl. Med. 62:149-155.

[1012] # 18 F]PSMA-1007 is known and is disclosed in Cardinale et al., J. Nucl. Med. 2017:58:425-431.

[1013] 61 Cu]Cu-NODAGA-PSMA-I&T and 61 Cu]Cu-DOTAGA-PSMA-I&T have the same level of lipophilicity. These two 61 Cu-labeled PSMA radiotracers are both more lipophilic than 68 Ga]Ga-PSMA-11 and 18F ​​F-PSMA-1007 (a PET tracer approved for PSMA imaging) (Hennrich U and Eder M Pharmaceuticals 2021; 14:713) is more lipophilic. A reported higher lipophilicity of 68 Ga]Ga-PSMA-11 is beneficial for PSMA-based radiotracers (Wirtz M et al., EJNMMI Res 2018). In addition, 61 Cu complexation has no significant effect on the lipophilicity / hydrophilicity of the radiotracer and is at the same level as the 68 Ga counterpart. Similarly, 61 Cu]Cu-NODAGA-TOC and 61 Cu]Cu-DOTA-TOC have the same level of lipophilicity and are more lipophilic than 68 Ga]Ga-DOTA-TOC used in clinics, and among them 61 Cu]Cu-NODAGA-LM3 has the strongest lipophilicity. All 61 Cu-labeled FAPI constructs have roughly the same lipophilicity as each other.

[1014] Example 5 - Binding Affinity of PSMA Ligands and Somatostatin Analogs and nat Cu Complexed NODAGA Constructs, DOTAGA Constructs and DOTA Constructs and Comparison with Reference Compounds

[1015] By determining IC 50 (the concentration of the test construct that results in 50% inhibition of the specific binding of the reference radioligand to the same molecular target), the affinity was measured.

[1016] In the case of PSMA constructs, radioiodinated ((S)-1-carboxy-5-(4-(- 125 I-iodo-benzamido)pentyl)carbamoyl)-L-glutamic acid ( 125 I-BA]KuE) was used as the reference radioligand. The assay was performed on LNCaP cells seeded in 24-well plates (1.5 X 105 cells / well). In the presence of 0.2 nM 125 I-BA]KuE, the cells were incubated with increasing concentrations of each nat Cu conjugate (ranging from 0.1 to 100 nM). After incubation on ice for 1 hour, the unbound (free) 125I-BA]KuE and the cells were detached with 1 M NaOH and counted (bound radioligand). Nonspecific binding was defined as the amount of binding activity in the presence of a high excess (10 μM) of the blocker 2-(phosphonomethyl)pentanedioic acid (2-PMPA).

[1017] In the case of the somatostatin construct, 125 I-labeled Tyr-somatostatin-14 ( 125 I-SS-14) was used as the reference radioligand. The assay was performed on a 96-well plate with a membrane suspension of HEK cells expressing human SST2 (HEK-SST2). The cell membrane was incubated with increasing concentrations of each nat Cu construct (ranging from 0.001 to 100 nM) in the presence of 0.05 nM 125 I-SS-14. After incubation at 37 °C for 1 hour, filtration was then carried out using a Brandel 48-well cell harvester. The filters containing the cell membrane (bound radioligand) were collected for measurement. Nonspecific binding was defined as the amount of binding activity in the presence of a 1,000-fold excess of SS-14.

[1018] Free and bound radioligands were quantitatively analyzed using a gamma counter. The data were analyzed using GraphPad Prism 9 software, and the IC 50 values were calculated using the “log(inhibitor) vs response” equation, based on specific binding = total binding - nonspecific binding. 50 The IC

[1019] values were expressed in nM and are reported in Table 18. 50 Table 18. The IC 125 values were determined by a competitive assay. The PSMA constructs were evaluated using the radioligand 125 I-BA]KuE at a concentration of 0.2 nM after incubation with LNCaP cells on ice for 1 hour, and the somatostatin constructs were evaluated using the radioligand

[1020] I]-Tyr-somatostatin-14 at a concentration of 0.05 nM after incubation with HEK-SST2 membranes at 37 °C for 1 hour. The results are expressed as the mean ± standard deviation (SD) of at least two independent experiments, performed in triplicate for each experiment. 50 Table 18: IC

[1021] <![CDATA nat Cu-complexed construct]]> <![CDATA[IC 50 (nM)]]> <![CDATA nat Cu-DOTAGA-PSMA-I&T]]> 11.2±2.3 <![CDATA nat Cu-NODAGA-PSMA-I&T]]> 9.3±1.8 <![CDATA nat Ga-PSMA-11]]> 2.4±0.4 <![CDATA nat Cu-DOTA-TOC]]> 0.23±0.02 <![CDATA nat Cu-NODAGA-TOC]]> 0.34±0.04 NODAGA-LM3 17.8±2.0 <![CDATA nat Cu-NODAGA-LM3]]> 17.7±2.2 <![CDATA nat Ga-DOTA-TOC]]> 0.18±0.02 Somatostatin-14 0.11±0.02

[1022] In both nat Cu-complexed PSMA constructs and bothnat Between the Cu-complexed TOC somatostatin analogues, the exchange of the chelator from DOTAGA (the reference construct DOTAGA-PSMA-I&T used in the clinic) and DOTA (the reference construct DOTA-TOC used in the clinic) to the chelator NODAGA (NODAGA-PSMA-I&T and NODAGA-TOC, respectively) did not impede nat the affinity of the Cu-complexed constructs for their molecular targets (PSMA and SST2, respectively). nat The IC 50 values of the Cu-complexed NODAGA constructs were in a similar low nanomolar range, indicating very high affinity, comparable to the corresponding DOTAGA and DOTA constructs as well as the reference molecules nat Ga-PSMA-11 (in the case of the PSMA I&T construct) and nat Ga-DOTA-TOC and the natural hormone somatostatin-14 (in the case of the TOC and LM3 constructs).

[1023] Complexation of Cu (or radiolabeling with 61 Cu) did not impede the affinity of the NODAGA-LM3 construct for its molecular target (SST2), as indicated by the unchanged IC nat values of NODAGA-LM3 and 50 Cu-NODAGA-LM3.

[1024] Example 6 - 61 In vitro cellular uptake of

[1025] In vitro cellular uptake studies were performed using intact cells seeded in 6-well plates overnight. On the day of the experiment, the cells were washed and incubated with each of the 61 Cu]Cu radiolabeled tracers at different time points, either alone or in the presence of blockers to distinguish specific and non-specific uptake. At each study time point, the medium containing unbound (free) radiolabeled tracer was removed, and the cells were then washed twice with ice-cold phosphate-buffered saline. The cells were then treated with ice-cold glycine solution (0.05 M, pH 2.8) for 2 X 5 minutes to strip the cell surface-bound radiolabeled tracer (releasing acid). Thereafter, the cells containing internalized radiolabeled tracer were stripped with 1 M NaOH at 37 °C and collected for measurement. After subtracting the non-specific values, the amount of specifically cell surface-bound and internalized radiolabeled tracer was expressed as a percentage of the total applied activity.

[1026] 61 Cu]Cu-DOTAGA-PSMA-I&T and​61 Cu]Cu-NODAGA-PSMA-I&T (0.5 nM), and this was compared with 68 Ga]Ga-counterparts. 2-(Phosphonomethyl)-pentanedioic acid (2-PMPA, 10 μM) was used to determine non-specific binding ( Figure 14 ).

[1027] was evaluated in HEK-SST2 cells 61 Cu]Cu-DOTA-TOC and 61 Cu]Cu-NODAGA-TOC (2.5 nM) and these were compared with their 68 Ga]Ga-counterparts. Somatostatin-14 (SS-14, 25 μM) was used to determine non-specific binding.

[1028] was evaluated in HT-1080.hFAP (FAP-positive) and HT-1080.wt (FAP-negative) cells 61 Cu]Cu-NODAGA-F1, 61 Cu]Cu-NODAGA-F3, 61 Cu]Cu-NODAGA-F2, 61 Cu]Cu-NODAGA-F4 and 61 Cu]Cu-NODAGA-FAPI-46 (0.2 nM).

[1029] The internalized fraction and cell surface binding fraction of the tested radiotracers are reported in Tables 19, 20 and 21.

[1030] 61 Cell uptake of Cu-labelled PSMA-I&T constructs and their 68 Ga-counterparts and distribution between the cell surface (cell membrane-bound) fraction and the internalized fraction (Table 19). Values are expressed as a percentage of the applied activity and refer to the specific uptake calculated by subtracting the non-specific value (determined in the presence of 10 μM 2-PMPA) from the total value (specific value = total value - non-specific value).

[1031] Table 19: Cell uptake and distribution

[1032]

[1033] n.d. Not determined

[1034] 61 Cu-labelled PSMA radiotracers showed time-dependent uptake in PSMA-expressing cells and, at 37 °C, the distribution between the cell surface (membrane) fraction and the internalized fraction was approximately equal.61 Cu]Cu-NODAGA-PSMA-I&T showed a 61 Cu]Cu-DOTAGA-PSMA-I&T had slightly lower but not significant cell surface binding and internalization. 61 Cellular uptake of Cu-labeled PSMA radiotracer constructs and their 68 The Ga counterparts were in the same range. The above findings lead to the conclusion that, overall, exchanging chelators or radionuclides did not impede PSMA-mediated cellular uptake in vitro.

[1035] Table 20. 61 Cu-labeled somatostatin analogs 68 Cellular uptake of Ga-labeled somatostatin analogs and distribution between the cell surface (cell membrane-bound) fraction and the internalized fraction. Values ​​are expressed as a percentage of the applied activity and refer to the specific uptake calculated after subtracting the nonspecific value (measured in the presence of 25 μM somatostatin-14) from the total value (specific value = total value - nonspecific value).

[1036] Table 20. Cellular uptake and distribution

[1037]

[1038] At 37 °C 61 The Cu-labeled TOC radiotracer was almost completely internalized by cells expressing SST2 in a time-dependent manner, with only negligible amounts remaining on the cell surface (cell membrane). 61 Observations between Cu radiotracers and their correspondence 68 Comparison of the Ga counterparts was consistent with the findings above for the PSMA constructs.

[1039] Table 21. 61 Cellular uptake of Cu-labeled FAPI analogs and distribution between the cell surface (cell membrane-bound) fraction and the internalized fraction. Values ​​are expressed as a percentage of the applied activity and refer to the specific uptake calculated after subtracting the nonspecific value (measured in the presence of the non-FAP-expressing cell line HT-1080.wt) from the total value (specific value = total value - nonspecific value).

[1040] Table 21. Cellular uptake and distribution

[1041]

[1042]

[1043] At 37 °C 61The Cu-labeled FAP radiotracer is rapidly and almost completely internalized by cells expressing human FAP, with only negligible amounts remaining on the cell surface (cell membrane).

[1044] Example 7 - Tumor Xenografts

[1045] Six- to eight-week-old athymic nude Foxn1nu / Foxn1+ mice were subcutaneously injected in the flank with LNCaP cells (107 cells / 200 μL) suspended in a 1:1 medium and Matrigel, or with HEK-SST2 cells (107 cells / 100 μL) suspended in sterile phosphate-buffered saline, or with a dual injection of HT-1080.hFAP cells (5x106 cells / 100 μL, right shoulder) and HT-1080.wt cells (5x106 cells / 100 μL, left shoulder). Before the experiment began, the tumors were allowed to grow for 1 - 3 weeks. LNCap xenografts were used to evaluate PSMA-based radiotracers, SST2 xenografts were used to evaluate somatostatin-based radiotracers, and HT-1080.hFAP and HT-1080.wt were used to evaluate FAP inhibitor-based radiotracers.

[1046] Example 8 - PET / CT Imaging

[1047] The test radiotracer was intravenously injected via the tail vein into tumor xenograft mice. 100 μL / 400 pmol / 4 - 8 MBq of the Cu-labeled PSMA radiotracer was injected into LNCap xenografts 61 100 μL / 200 pmol / 3 - 5 MBq of the Cu-labeled somatostatin radiotracer was injected into HEK-SST2 xenografts 61 100 μL / 500 pmol / 10 - 12 MBq of the Cu-labeled FAP inhibitor radiotracer was injected into HT-1080 xenografts 61Cu-labeled FAP inhibitor radiotracer. Mice were anesthetized with 1.5% isoflurane and dynamic PET scans were performed during the 1-hour period after injection of the radiotracer. Mice were euthanized with carbon dioxide 4 hours after injection, the bladder was emptied mechanically, and static PET scans were acquired for 30 minutes. PET images were acquired using a β-CUBE PET scanner system (MOLECUBES, Ghent, Belgium) and attenuation correction and reconstruction were performed using VivoQuant version 4.0 software. CT scans were obtained in the supine head-first position using a NanoSPECT / CTTM scanner (Bioscan). First, scout images of the whole mouse and helical CT scans were obtained using the following parameters: X-ray tube current: 177 μA, X-ray tube voltage: 45 kVp, 90 seconds, 180 frames per rotation, pitch 1. CT images were reconstructed using CTReco (version r1.146) with a standard filtered back-projection algorithm (exact cone beam) and post-filtering (RamLak, 100% frequency cut-off) to obtain a pixel size of 0.2 mm. The registered PET / CT images were visualized using maximum intensity projection (MIP) with InVivoScope (version 1.43, Bioscan Inc.). The results will be presented in the following examples.

[1048] Example 9 - Biodistribution Study

[1049] In tumor xenograft mice, quantitative biodistribution studies were performed after the radiotracers to be tested below were intravenously injected into the tail vein: 61 [[Cu]]Cu-DOTAGA-PSMA-I&T and 61 [[Cu]]Cu-NODAGA-PSMA-I&T at an injection volume of 100 μL / 200 pmol / 1.5 - 3.5 MBq in LNCaP xenografts, 61 [[Cu]]Cu-NODAGA-TOC or 61 [[Cu]]Cu-DOTA-TOC at an injection volume of 100 uL / 200 pmol / 1.5 - 4.5 MBq in HEK-SST2 xenografts and 61 [[Cu]]Cu-NODAGA-F1, 61 [[Cu]]Cu-NODAGA-F3, 61 [[Cu]]Cu-NODAGA-F2, 61 [[Cu]]Cu-NODAGA-F4 or 61Cu]Cu-NODAGA-FAPI-46 was injected at a dose of 100 uL / 500 pmol / 0.8 - 1.2 MBq in HT-1080.hFAP and HT-1080.wt xenograft tumors. Mice were randomly assigned to groups and sacrificed at 1 hour and 4 hours post-injection. Target organs were collected, rinsed, blotted dry, weighed, and counted in a gamma counter. Results were expressed as percentage of injected activity per gram (%IA / g), representing the mean ± standard deviation for N = 4 - 8 mice per group, and were extrapolated from counts of aliquots taken from the injection solution as a standard.

[1050] The results are shown in Tables 22, 23, and 24A, 24B, and 24C.

[1051] Table 22. At 1 hour and 4 hours post-injection 61 Cu]Cu-NODAGA-PSMA-I&T and 61 Cu]Cu-DOTAGA-PSMA-I&T biodistribution data in LNCaP xenograft tumors. Results are expressed as the mean percentage of injected activity per gram of tissue (%IA / g) ± standard deviation (SD).

[1052]

[1053]

[1054] *N = 8, #N = 4

[1055] 61 Cu]Cu-NODAGA-PSMA-I&T and 61 Cu]Cu-DOTAGA-PSMA-I&T showed high accumulation in PSMA-positive (LNCaP) tumors and PSMA-positive tissues such as the kidney and salivary gland. Compared with 61 Cu]Cu-DOTAGA-PSMA-I&T, 61 Cu]Cu-NODAGA-PSMA-I&T showed higher tumor uptake and also higher kidney uptake, while 61 Cu]Cu-DOTAGA-PSMA-I&T showed undesirably higher uptake in the liver, stomach, intestine, and blood, resulting in a higher overall background. Among the two radiotracers, 61 Cu]Cu-NODAGA-PSMA-I&T showed an advantage as it had higher tumor uptake and an improved tumor-to-non-tumor organ ratio (except for the tumor-to-kidney ratio at 4 hours). Between the two study time points of 1 hour and 4 hours post-injection, 4 hours showed an advantage as the tumor-to-background ratio was significantly improved, see​Figure 12 .

[1056] Table 23. One hour and four hours after injection 61 Cu]Cu-NODAGA-TOC and 61 Cu]Cu-DOTA-TOC biodistribution study in HEK-SST2 xenograft tumors. Results are expressed as the mean percentage of injected activity per gram of tissue (% IA / g) ± standard deviation (SD).

[1057]

[1058] * N = 5, #N = 7, ￥N = 4

[1059] 61 Cu]Cu-NODAGA-PSMA-I&T and 61 Cu]Cu-DOTAGA-PSMA-I&T showed high accumulation in SST2-positive (HEK-SST2) tumors and SST2-positive tissues (such as the stomach and pancreas) and were eliminated via the kidneys. Compared with 61 Cu]Cu-DOTA-TOC, 61 Cu]Cu-NODAGA-TOC showed higher renal uptake, while 61 Cu]Cu-DOTA-TOC showed undesirably higher uptake in the liver, stomach, pancreas, and intestine, as well as in the blood, resulting in a higher overall background. Among the two radiotracers, 61 Cu]Cu-NODAGA-TOC showed an advantage due to its improved tumor-to-non-tumor organ ratio (except for the tumor-to-kidney ratio). Between the two study time points, 4 hours after injection was favorable compared to 1 hour because the tumor-to-background ratio was significantly improved.

[1060] The observations in PSMA xenograft tumors and SST2 xenograft tumors were consistent and represented the 61 Cu]Cu-NODAGA chelate relative to 61 Cu]Cu-DOTAGA or 61 Cu]Cu-DOTA chelates in combination with different targeting moieties, as well as 61 Cu (half-life 3.33 hours) relative to 68 Ga (half-life 68 minutes) routinely used in clinical practice, by imaging at 4 hours instead of 1 hour.

[1061] 61 ​​Cu]Cu-NODAGA-F1 showed high accumulation in FAP-positive (HT-1080.hFAP) tumors and murine-FAP-positive tissues such as synovial tissues in joints (e.g., joints associated with femurs).

[1062] Table 24A. At 1 hour and 4 hours post-injection 61 Cu]Cu-NODAGA-F1 and 61 Cu]Cu-NODAGA-F3 biodistribution studies in HT-1080.hFAP and HT-1080.wt xenograft tumors. Results are expressed as mean percentage of injected activity per gram of tissue (%IA / g) ± standard deviation (SD).

[1063]

[1064]

[1065] Table 24B. At 1 hour and 4 hours post-injection 61 Cu]Cu-NODAGA-F2 and 61 Cu]Cu-NODAGA-F4 biodistribution studies in HT-1080.hFAP and HT-1080.wt xenograft tumors. Results are expressed as mean percentage of injected activity per gram of tissue (%IA / g) ± standard deviation (SD).

[1066]

[1067]

[1068] Table 24C. At 1 hour and 4 hours post-injection 61 Cu]Cu-NODAGA-FAPI-46 biodistribution studies in HT-1080.hFAP and HT-1080.wt xenograft tumors. Results are expressed as mean percentage of injected activity per gram of tissue (%IA / g) ± standard deviation (SD).

[1069]

[1070] 61 Cu]Cu-NODAGA-F1, 61 Cu]Cu-NODAGA-F3, 61 Cu]Cu-NODAGA-F2, 61 Cu]Cu-NODAGA-F4 and 61 ​Cu]Cu-NODAGA-FAPI-46 showed high accumulation in FAP-positive (HT-1080.hFAP) tumors and mouse-FAP-positive tissues such as synovial tissues in joints (e.g., joints associated with femur).

[1071] Example 10 - Specificity study

[1072] was evaluated in mice with LNCaP xenografts 61 Cu]Cu-NODAGA-PSMA-I&T and 61 the specificity of Cu]Cu-DOTAGA-PSMA-I&T. First, 1.3 μmol (300 μg) of 2-phosphonomethylpentanedioic acid (2-PMPA) was injected as a blocker, and then the radiotracer, such as 61 Cu]Cu-DOTAGA-PSMA-I&T (100 μL / 400 pmol / 4 - 8 MBq) or 61 Cu]Cu-NODAGA-PSMA-I&T (100 μL / 400 pmol / 4 - 8 MBq). One hour after injection, PET / CT images were acquired as described in Example 8. In addition, PET / CT images of xenograft tumors were also acquired after injection of 61 Cu]CuCl2 (100 μL / 7 MBq) to evaluate the whole-body distribution of free (uncomplexed) 61 Cu. The results are shown in Figure 10 , subfigures A and B. L = liver; K = kidney; T = tumor; Bl = bladder; I = intestine.

[1073] 61 Cu]Cu-NODAGA-PSMA-I&T and 61 Cu]Cu-DOTAGA-PSMA-I&T showed significantly lower uptake in PSMA-positive tumors and kidneys in xenograft tumors pre-injected with 2-PMPA, indicating PSMA-mediated uptake (specificity) ( Figure 12 , subfigures A and B). The PET / CT images of uncomplexed 61 Cu ( Figure 12 , subfigure C) showed accumulation in the abdomen, especially in the liver and intestine, which was comparable to the uptake on the PET / CT images of 61 Cu]Cu-DOTAGA-PSMA-I&T (except for tumors and kidneys), but different from the whole-body distribution of 61 Cu]Cu-NODAGA-PSMA-I&T ( Figure 11 , subfigures A and B). Compared with 61 Cu]Cu-NODAGA-TOC ( Figure 13 ​, sub - figure C and sub - figure D) or 61 Cu]Cu-(R)-NODAGA-LM3( Figure 13 , compared with sub - figure E and sub - figure F), similarly 61 Cu]Cu-DOTA-TOC (PET / CT images( Figure 13 , the observations of sub - figure A and sub - figure B), are the same as 61 Cu]CuCl2. This direct comparison shows that 61 Cu]Cu-NODAGA radiotracer has high in - vivo stability and thus superiority, while conversely 61 Cu]Cu-DOTAGA and 61 Cu]Cu-DOTA radiotracers have low in - vivo stability.

[1074] Example 11 - Pharmacokinetics in tumor - free mice

[1075] 61 / 64 Cu]Cu-NODAGA-PSMA-I&T (Table 25) and 61 Cu] / 64 Cu]Cu-NODAGA-TOC (Table 26) pharmacokinetic studies were performed in healthy female BALB / c mice from 1 hour to 24 hours after injection of 100 μL / 200 pmol / 4 MBq of the corresponding radiotracer. At the 1 - hour and 4 - hour time points, 61 Cu (half - life 3.33 hours) was used, and at the 12 - hour and 24 - hour time points, 64 Cu (half - life 12.7 hours) was used. The biodistribution at the study time points was carried out as described in Example 9. Since the biodistribution in nude mice is the same as that in healthy mice, the data were combined with the results obtained from the xenograft tumor group at 1 hour and 4 hours after injection. The results were expressed as described in Example 10.

[1076] Table 25. Biodistribution data of 61 Cu] / 64 Cu]Cu-NODAGA-PSMA-I&T at 1, 4, 12, and 24 hours after injection. The results are expressed as the mean percentage of injected activity per gram of tissue (% IA / g) ± standard deviation (SD).

[1077] Organ 1 hour * 4 hours # 12 hours ¥ 24 hours ¥ Blood 0.33±0.09 0.11±0.03 0.11±0.01 0.08±0.01 Heart 0.49±0.12 0.25±0.06 0.26±0.05 0.21±0.02 Lung 1.49±0.45 0.68±0.22 0.52±0.11 0.32±0.12 Liver 1.12±0.25 0.88±0.25 0.96±0.18 0.84±0.11 Pancreas 1.37±0.90 0.55±0.16 0.28±0.04 0.17±0.03 Spleen 9.33±3.81 2.35±1.45 1.40±0.57 0.58±0.15 Stomach 1.12±0.15 0.72±0.15 0.52±0.03 0.31±0.05 Intestine 2.11±0.85 1.12±0.48 0.94±0.41 0.46±0.11 Adrenal gland 14.38±4.39 7.31±2.76 2.99±0.93 1.17±0.22 Kidney 124±21 94±12 60±9 16.1±4.9 Muscle 0.99±0.30 0.45±0.18 0.25±0.05 0.08±0.02 Femur 2.48±0.97 1.34±0.38 0.50±0.10 0.20±0.05 Salivary gland 1.89±0.28 0.58±0.12 0.39±0.05 0.22±0.05

[1078] *N = 16, #N = 13, ￥N = 5

[1079] Due to the excretion pathway and PSMA expression, 61 / 64 ​Cu]Cu-NODAGA-PSMA-I&T has a rapid blood clearance rate and high accumulation in the kidneys. Other organs with significant uptake include the adrenal glands, spleen, and intestine. The radiotracer washes out of all organs except the kidneys within 24 hours.

[1080] Table 26. At 1, 4, 12, and 24 hours after injection 61 / 64 Biodistribution data of Cu]Cu-NODAGA-TOC. Results are expressed as the mean percentage of injected activity per gram of tissue (% IA / g) ± standard deviation (SD).

[1081] Organ 1 hour * 4 hours # 12 hours ¥ 24 hours ¥ Blood 0.24±0.08 0.04±0.02 0.04±0.01 0.03±0.00 Heart 0.17±0.03 0.07±0.02 0.09±0.02 0.07±0.02 Lung 1.07±0.17 0.50±0.24 0.51±0.12 0.27±0.09 Liver 0.35±0.08 0.28±0.08 0.37±0.09 0.26±0.02 Pancreas 2.71±0.40 0.60±0.19 0.14±0.03 0.07±0.01 Spleen 0.23±0.04 0.10±0.03 0.10±0.02 0.07±0.02 Stomach 2.62±0.48 1.35±0.26 0.75±0.19 0.26±0.04 Intestine 0.96±0.12 0.69±0.19 0.57±0.07 0.31±0.05 Adrenal gland 1.06±0.24 0.63±0.22 0.32±0.20 0.18±0.10 Kidney 17.2±4.46 7.64±3.85 2.46±0.85 0.66±0.15 Muscle 0.16±0.05 0.07±0.03 0.02±0.01 0.01±0.00 Femur 0.45±0.14 0.28±0.11 0.11±0.04 0.06±0.01 Pituitary gland 3.39±1.11 2.71±1.84 0.48±0.25 0.43±0.29

[1082] *N = 10, #N = 12, ￥N = 5

[1083] 61 / 64 Cu]Cu-NODAGA-TOC has a very rapid blood clearance rate and is almost completely excreted from the body within 24 hours.

[1084] Example 12 - 61 In vivo comparison of Cu]Cu-NODAGA radiotracer with reference compounds

[1085] Under the same experimental conditions, 61 The biodistribution of the Cu]Cu-NODAGA radiotracer was compared with reference compounds used in patients. Mice were randomly assigned to groups, injected with the radiotracer under study, and sacrificed at 1 hour and 4 hours after injection of the radiotracer under study. The target organs were collected, rinsed, blotted dry, weighed, and counted in a gamma counter. Results are expressed as the percentage of injected activity per gram (% IA / g), representing the mean ± standard deviation for all mice in each group, and were extrapolated from counts of aliquots taken from the injected solution. Table 27 and Figure 31 and Figure 32 show 61 Cu]Cu-NODAGA-PSMA-I&T (100 μL / 200 pmol / 1.5 - 3.5 MBq) vs 68 Ga]Ga-PSMA-11 (100 μL / 200 pmol / 3 - 5 MBq), vs 18 F]PSMA-1007 (100 μL / 70 pmol / 15 MBq) in a direct comparison, Table 28 shows at 1 hour after injection 61 Cu]Cu-NODAGA-PSMA-TOC vs 68 Ga]Ga-DOTA-TOC in a direct comparison, and Figure 33 and Figure 34 shows at 1 hour after injection 61 ​Cu]Cu-NODAGA-LM3 and 68 Ga]Ga-DOTA-TOC direct comparison.

[1086] Table 27. One hour after injection in LNCap xenograft mice 61 Cu]Cu-NODAGA-PSMA-I&T and 68 Ga]Ga-PSMA-11 biodistribution comparison in LNCap xenograft mice at 1 hour and 4 hours after injection 18 F]PSMA-1007 comparative biodistribution, and the ratio of selective tumor to non-tumor organs. Results are expressed as the mean percentage of injected activity per gram of tissue (% IA / g) ± standard deviation (SD).

[1087]

[1088]

[1089] One hour after injection 61 Cu]Cu-NODAGA-PSMA-I&T and the reference radiotracer used in clinical practice 68 Ga]Ga-PSMA-11 shows comparable efficacy ( Figure 31 ). However, 61 Cu]Cu-NODAGA-PSMA-I&T provides the possibility of imaging at 4 hours after injection, when the tumor-to-background ratio increases significantly. This is expected to result in significantly better image contrast, thus improving diagnostic sensitivity. 61 Cu]Cu-NODAGA-PSMA-I&T is also comparable to other reference radiotracers used in clinical practice 18 F]PSMA-1007, but there are some exceptions, such as higher and persistent spleen uptake of 18 F]PSMA-1007 at 1 hour and 4 hours after injection. At the later time point of the study (4 hours after injection), 61 Cu]Cu-NODAGA-PSMA-I&T has higher tumor uptake than 18 F]PSMA-1007 used in clinical practice (10.7 ± 3.3 vs 6.28 ± 2.19 % IA / g, p = 0.0145), and the tumor-to-background (tumor-to-blood and tumor-to-muscle) ratios are better.

[1090] Table 28. One hour after injection 61 Cu]Cu-NODAGA-TOC and 68Comparative biodistribution of [ [

[1091] Organ <![CDATA 61 Cu]Cu-NODAGA-TOC * > <![CDATA 68 Ga]Ga-DOTA-TOC # > Blood 0.22±0.04 0.63±0.09 Heart 0.16±0.04 0.27±0.03 Lung 1.09±0.20 1.68±0.32 Liver 0.29±0.04 0.58±0.07 Pancreas 2.59±0.49 4.77±1.16 Spleen 0.22±0.05 0.42±0.05 Stomach 2.34±0.43 3.73±0.36 Intestine 0.92±0.12 1.39±0.28 Adrenal gland 0.99±0.17 2.57±0.78 Kidney 12.5±2.25 8.37±0.84 Muscle 0.16±0.06 0.23±0.09 Bone 0.46±0.17 0.49±0.07 Pituitary gland 3.80±1.35 3.29±0.63 HEK-SST2 8.88±3.19 6.64±1.11 Ratio 1 hour (4 hours) 1 hour Tumor / blood 40(185) 11 Tumor / liver 31(27) 12 Tumor / kidney 0.7(1.7) 0.8 Tumor / muscle 56(106) 29

[1092] *N = 5, #N = 4

[1093] 61 [ [ 68 [ [ Figure 34 。

[1094] Overall, 61 [ [ 61 [ [ 61 [ [ 68 [ [ 61 [ [

[1095] Example 13: Synthesis of FAP Inhibitors

[1096] 5.1.11. Synthesis of (S)-N1-(2-aminoethyl)-N4-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)succinimide (1)

[1097] Step 1: (S)-6-amino-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (A)

[1098]

[1099] ​Two precursors (purchased from AstaTech) were dissolved in DMF together with HATU, and then DCM was added. DIPEA was added dropwise, and the reaction was monitored by LC / MS. The reaction was completed in less than 1 hour. The crude product was concentrated, diluted with water / acetonitrile 85:15, and purified directly by HPLC (LCMS-2020 Shimadzu system, equipped with a Gemini C-6 Phenyl column (10X250 mm, 5 μm particle size). The gradient used was 5 - 80% solvent B in 15 minutes (A = H2O [0.1% TFA], B = ACN [0.1% TFA], flow rate was 5.0 mL / min), to obtain pure red powder A (38 μg, yield 84%).

[1100] Step 2: Synthesis of (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoic acid (B)

[1101]

[1102] (S)-6-Amino-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (A) and succinic anhydride were dissolved in THF. DIPEA was added dropwise, and the reaction mixture was stirred overnight and detected by LC / MS. The crude product was purified directly by HPLC (LCMS-2020 Shimadzu system, equipped with a Gemini C-6 Phenyl column (10X 250mm, 5 μm particle size). The gradient used was 5 - 80% solvent B in 8 minutes (A = H2O [0.1% TFA], B = ACN [0.1% TFA], flow rate was 5.0 mL / min), to obtain yellow powder B (32.7 μg, yield 68%).

[1103] Step 3: (S)-N1-(2-aminoethyl)-N4-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)succinimide (F1)

[1104]

[1105] (S)-6-Amino-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (B) and succinic anhydride were dissolved in THF. DIPEA was added dropwise, and the reaction mixture was stirred overnight and detected by LC / MS. The crude product was purified directly by HPLC (5 to 80% in 8 minutes), to obtain yellow powder F1 (32.7 μg, yield 68%).

[1106] 5.1.12. Synthesis of (S)-N1-(2-aminoethyl)-N4-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)-N4-methylsuccinamide (2)

[1107] As shown in Scheme 2, F2 was prepared:

[1108] Scheme 2

[1109]

[1110] Step 1: Under N2, at 0 - 5 °C, SOCl2 (26.4 g, 222 mmol, 16.1 mL) was added in one portion to a mixture of compound A (4.17 g, 22.2 mmol) in MeOH (84.0 mL). The reaction mixture was stirred at 0 - 5 °C for 0.5 h. The mixture was heated to 75 °C and stirred for 12 h. SOCl2 (26.4 g, 222 mmol, 16.1 mL) was added to the mixture, and it was stirred at 75 °C for 12 h. SOCl2 (26.4 g, 222 mmol, 16.1 mL) was added to the mixture, and it was stirred at 75 °C for 12 h. SOCl2 (13.2 g, 111 mmol, 8.04 mL) was added to the mixture, and it was stirred at 75 °C for 12 h. LC-MS showed detection of a main peak with the desired mass. The mixture was concentrated in vacuo. The crude product was triturated with MeCN (300 mL) at 20 °C for 1 h to give brown solid compound B (7.05 g, crude). 1H NMR: (400 MHz, DMSO-d6) δ 8.81 (d, J = 4.8 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 4.8 Hz, 1H), 7.82 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H). LC-MS (LCMS-2020 Shimadzu system, equipped with Gemini C-6Phenyl column (3.5X250 mm, 5 μm particle size). The gradient used was 5 - 80% solvent B (A = H2O [0.1% TFA], B = ACN [0.1% TFA]) in 8 min, flow rate was 1.0 mL / min, product: RT = 1.262 min).

[1111] Step 2:To a solution of B (7.02 g, 34.7 mmol) in MeOH (100 mL) and Boc2O (100 mL) was added TEA (7.03 g, 69.4 mmol), and the mixture was stirred at 25 °C for 12 h. LCMS showed that compound B had been consumed and a peak with the desired MS was detected. The mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1, compound C Rf = 0.35) to give compound C as a brown solid (4.36 g, yield 41.5%). 1H NMR: (400 MHz, CDCl3) δ 8.89 (d, J = 4.4 Hz, 1H), 8.78 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H), 7.96 - 7.89 (m, 2H), 6.83 (s, 1H), 4.04 (s, 3H), 1.57 (s, 9H).

[1112] Step 3: At 0 °C, NaH (778 μg, 19.5 mmol, purity 60%) was added portionwise to a solution of compound C (3.36 g, 11.1 mmol) in DMF (84.0 mL), and the mixture was stirred at 25 °C for 20 min. At 25 °C, MeI (3.94 g, 27.8 mmol) was added to the reaction mixture and the mixture was stirred at 25 °C for 2 h. LCMS (ET60385-17-P1A3, product retention time = 0.562 min) showed that compound C had been consumed and a peak with the desired MS was detected. The reaction mixture was cooled to 0 °C, quenched with brine (80.0 mL), and extracted with EtOAC (3 × 100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give compound D as a brown solid (4.78 g, crude).

[1113] Step 4:To a solution of compound D (4.78 g, 15.1 mmol) in DCM (50.0 mL) was added dropwise TFA (8.61 g, 75.5 mmol), and the mixture was stirred at 25 °C for 12 h. LCMS showed that compound D had been consumed and a peak with the desired MS was detected. The reaction mixture was quenched with saturated NaHCO3 (50.0 mL) and extracted with DCM (3 × 40.0 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1, product Rf = 0.40) to give compound E as a brown solid (2.51 g, yield 76.8%). 1H NMR: ET60385-19-P1A1 (400 MHz, CDCl3) δ 8.67 (d, J = 4.4 Hz, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.85 (d, J = 4.4 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.17 - 7.14 (m, 1H), 4.02 (s, 3H), 3.01 (s, 3H).

[1114] Step 5: To a solution of compound E (500 μg, 2.31 mmol) in THF (4.00 mL) was added tetrahydrofuran-2,5-dione (231 μg, 2.31 mmol), and the reaction mixture was stirred at 50 °C for 12 h. LCMS showed that compound E had been consumed and a peak with the desired MS was detected. The mixture was concentrated in vacuo to give compound F as a brown solid (716 μg, crude). 1H NMR: ET60385-43-P1A1 (400 MHz, CDCl3) δ 9.10 (d, J = 4.0 Hz, 1H), 8.77 (d, J = 2.4 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 4.0 Hz, 1H), 7.66 - 7.64 (m, 1H), 4.06 (s, 3H), 3.42 (s, 3H), 2.69 - 2.66 (m, 2H), 2.51 - 2.50 (m, 2H).

[1115] Step 6:To a solution of compound F (716 μg, 2.26 mmol) in DMF (7.00 mL) was added TEA (343 μg, 3.40 mmol), HOBt (458 μg, 3.40 mmol), EDCI (650 μg, 3.40 mmol) and tert-butyl N-(2-aminoethyl)carbamate (398 μg, 2.49 mmol). The reaction mixture was stirred at 25 °C for 12 h. LCMS showed that compound F had been consumed and a peak with the desired MS was detected. The reaction mixture was quenched with saturated NaHCO3 (15.0 mL), extracted with DCM (25.0 mL × 3), and washed with brine (15.0 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give compound G (1.33 g, crude) as a brown solid.

[1116] Step 7: To a solution of compound G (1.33 g, 2.90 mmol) in Py. (20.0 mL) was added LiI (7.86 g, 58.6 mmol). The mixture was stirred at 110 °C for 4 h. LCMS showed that compound G had been consumed and a peak with the desired MS was detected. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*100mm#10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 1%-30%, 20 min) to give compound H (647 μg, yield 50.1%) as an off-white solid.

[1117] Step 8: To a solution of compound H (617 μg, 1.39 mmol) in DMF (6.00 mL) was added DIEA (717 μg, 5.55 mmol), HATU (791 μg, 2.08 mmol) and compound 6-1 (587 μg, 2.08 mmol, purity 80%, HCl). The mixture was stirred at 25 °C for 1 h. LCMS showed that compound H had been consumed and a peak with the desired MS was detected. The reaction mixture was quenched with saturated NaHCO3 (15.0 mL), extracted with DCM (25.0 mL × 3), and washed with brine (15.0 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give compound I (2.70 g, crude) as a brown solid.

[1118] Step 9:To a solution of Compound I (2.70 g, 4.39 mmol) in DCM (10.0 mL) was added TFA (41.5 g, 364 mmol), and the mixture was stirred at 25 °C for 1 hour. LCMS (ET60385-61-P1A4, product retention time = 0.490 min) showed that Compound I had been consumed completely, and a peak with the desired MS was detected. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*100 mm #10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 5%-35%, 20 min) to give Compound F2 (260 μg, yield 11.1%, purity 97.3%) as a brown solid. LCMS (LCMS-2020 Shimadzu system, equipped with Gemini C-6Phenyl column (3.5X250 mm, 5 μm particle size). The gradient used was 5-80% solvent B in 8 min (A = H2O [0.1% TFA], B = ACN [0.1% TFA]), flow rate was 1.0 mL / min, product RT = 0.493 min).

[1119] 5.1.13. Synthesis of (S)-N-(2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-oxo-4-(piperazin-1-yl)butanamido)quinoline-4-carboxamide (F3)

[1120]

[1121] (S)-4-((4-((2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutyric acid, HATU, and the amine were dissolved in DCM and DMF. DIPEA was added dropwise and the reaction was monitored. When all the coupling occurred, the crude product was concentrated slightly, then TIPS was added. TFA was added dropwise, and the mixture was checked by LC / MC until the reaction was complete. The crude product (F3) was used as it was.

[1122] 5.1.14. Synthesis of (S)-(fN-(2-(2-Cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(N-methyl-4-oxo-4-(piperazin-1-yl)butanamido)quinoline-4-carboxamide (F4)

[1123] As shown in Scheme 3, F4 was prepared:

[1124] Scheme 3

[1125]

[1126] Step 1: To a m...

Claims

1. A composition comprising a radiotracer, said radiotracer comprising: a chelating moiety, a copper radionuclide (*Cu) chelated by said chelating moiety, and a targeting moiety covalently linked to said chelating moiety.

2. The composition according to claim 1, wherein a compound is provided, wherein said compound has formula A: Wherein: is the chelating moiety; *Cu is 61 Cu, 62 Cu, 64 Cu or 67 Cu; L is a bond or a linking moiety; and V is said targeting moiety; n is an integer from 1 to 10, preferably 1.

3. The composition according to claim 1 or 2, wherein *Cu is in the (II) oxidation state.

4. The composition according to any one of claims 1 - 3, having a molar activity in the range of 1 to 250 MBq / nmol and / or wherein said composition has a radiochemical purity of 91% or higher.

5. The composition according to any one of claims 1 - 4, wherein said chelating moiety comprises 2 - 8 binding moieties.

6. The composition according to any one of claims 1 - 5, wherein one or more of said binding moieties are selected from thiol groups, amino groups, and carboxyl groups.

7. The composition according to claim 6, wherein one or more of said binding moieties are tertiary amines.

8. The composition according to any one of claims 1 - 7, wherein said chelating moiety comprises six binding elements selected from a combination of amino groups and carboxyl groups.

9. The composition according to any one of claims 1 - 8, wherein said chelating moiety conforms to formula 1: Wherein: R 1 、 R 2 and R 3 are each independently: C 2-6 alkyl, optionally substituted with one or more substituents selected from: oxo, mercapto, hydroxy, C 1-3 alkoxy, C 1-3 carboxy and C 1-3 alkylthio, including their deprotonated variants, depending on chelation to *Cu; and R 1 , R 2 and R 3 or at least one of the methylene carbons forming the nitrogen ring contains a point of connection to the linking group moiety (when L is the linking group moiety) or to the targeting moiety (when L is a bond).

10. The composition according to claim 9, wherein said chelating moiety conforms to formula 1' or formula 1'a: Among them represents the point connected to the linking group part (when L is the linking group part) or to the targeting part (when L is a bond).

11. The composition according to claim 10, wherein said chelating moiety conforms to formula 2, 2' or formula 2'2'a: wherein X 1 、X 2 and X 3 are each independently selected from: -OH, -NH2, and -SH, including their deprotonated variants, depending on chelation with *Cu; and Wherein any methylene group is optionally substituted by: oxo, thiol or hydroxyl.

12. The composition according to claim 11, wherein said chelating moiety conforms to formula 2i, 2'i, 2ii or 2iii:

13. The composition according to claim 9, wherein corresponds to formula II or II': Wherein: X 1 , X 2 and X 3 is independently selected from -OH, -NH2, and -SH, including their deprotonated variants, depending on chelation with *Cu; any methylene group is optionally substituted by oxo, thiol or hydroxyl; and Represents the point of connection to the linking moiety (when L is the linking moiety) or to the targeting moiety (when L is a bond).

14. The composition according to claim 13, wherein conforms to Formula II, X 1 , X 2 and X 3 are each independently selected from -OH, -NH2, and -SH, including their deprotonated variants, depending on chelation with *Cu; wherein any methylene group is optionally substituted by: oxo, thiol or hydroxyl; and wherein represents a point of connection with a linking moiety (when L is a linking moiety) or with a targeting moiety (when L is a bond).

15. The composition according to claim 14, wherein corresponds to Formula IIi, II’i, IIii or IIiii:

16. The composition according to any one of claims 1 - 15, wherein the chelating moiety comprises: Selected from DOTAGA (1,4,7,10 - tetraazacyclododecane, 1-(pentanedioic acid)-4,7,10 - triacetic acid), DOTA (1,4,7,10 - tetraazacyclododecane - 1,4,7,10 - tetraacetic acid), DOTASA (1,4,7,10 - tetraazacyclododecane - 1-(2 - succinic acid)-4,7,10 - triacetic acid), CB - DO2A (10 - bis(carboxymethyl)-1,4,7,10 - tetraazabicyclo[5.5.2]tetradecane), DEPA (7 - [2-(bis - carboxymethylamino)-ethyl]-4,10 - bis - carboxymethyl - 1,4,7,10 - tetraaza - cyclododecane - 1 - yl - acetic acid)), 3p - C - DEPA (2 - [(carboxymethyl)][5-(4 - nitrophenyl - 1 - [4,7,10 - tris(carboxymethyl)-1,4,7,10 - tetraazacyclododecane - 1 - yl]pent - 2 - yl)amino]acetic acid)), TCMC (2-(4 - isothiocyanatobenzyl)-1,4,7,10 - tetraaza - 1,4,7,10 - tetra-(2 - carbamoylmethyl)-cyclododecane), oxo - DO3A (1 - oxa - 4,7,10 - triazacyclododecane - 5 - S-(4 - isothiocyanatobenzyl)-4,7,10 - triacetic acid), p - NH2 - Bn - Oxo - DO3A (1 - oxa - 4,7,10 - tetraazacyclododecane - 5 - S-(4 - aminobenzyl)-4,7,10 - triacetic acid), TE2A ((1,8 - N,N′ - bis-(carboxymethyl)-1,4,8,11 - tetraazacyclotetradecane), MM - TE2A, DM - TE2A, CB - TE2A (4,11 - bis(carboxymethyl)-1,4,8,11 - tetraazabicyclo[6.6.2) hexadecane), CB-TE1A1P (4,8,11-tetraazacyclotetradecane-1-(methanephosphonic acid)-8-(methanecarboxylic acid)), CB-TE2P (1,4,8,11-tetraazacyclotetradecane-1,8-bis(methanephosphonic acid)), TETA (1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid), NOTA (1,4,7-triazacyclononane-N,N′,N″-triacetic acid), NODA (1,4,7-triazacyclononane-1,4-diacetate); NODAGA (1,4,7-triazacyclononane,1-pentanedioic acid-4,7-acetic acid), (NOTAGA)1,4,7-triazacyclononane-1,4-diyl)diacetic acid DFO (deferoxamine), NETA ([4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazacyclononane-1-yl}-acetic acid), TACN-TM (N,N',N”,tris(2-mercaptoethyl)-1,4,7-triazacyclononane), Diamsar (1,8-diamino-3,6,10,13,16,19-hexaazabicyclo(6,6,6)icosane, 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1,8-diamine), Sarar (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1,8-diamine), AmBaSar (4-((8-amino-3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1-ylamino)methyl)benzoic acid) and 4,4'-((3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane-1,8-diylbis(azanediyl))bis(methylene))dibenzoic acid (BaBaSar).

17. The composition according to claim 16, wherein the chelating moiety comprises: 2,2',2''-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (NOTA); 2,2'((2-(,7-bis-(carboxymethyl)-1,4,7-triazacyclononane-1-yl)ethyl)azanediyl)diacetic acid (NETA); 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA); 2,2'-(7-(1-carboxy-4-oxopentyl)-1,4,7-triazacyclononane-1,4-diyl)diacetic acid (NODAGA); 2-(4,7-bis(carboxymethyl)-1,4,7-triazacyclononane-1-yl)succinic acid (NODASA); (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) (DOTA); (1,4,7,10-tetraazacyclododecane,1-(glutaric acid)-4,7,10-triacetic acid) (DOTAGA); (1,4,7,10-tetraazacyclododecane,1-(succinic acid)-4,7,10-triacetic acid) (DOTASA).

18. The composition according to claim 17, wherein the chelating moiety comprises: 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA); 2,2'-(7-(1-carboxy-4-oxopentyl)-1,4,7-triazacyclononane-1,4-diyl)diacetic acid (NODAGA); 2-(4,7-bis(carboxymethyl)-1,4,7-triazacyclononane-1-yl)succinic acid (NODASA); (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) (DOTA); (1,4,7,10-tetraazacyclododecane,1-(glutaric acid)-4,7,10-triacetic acid) (DOTAGA); (1,4,7,10-tetraazacyclododecane,1-(succinic acid)-4,7,10-triacetic acid) (DOTASA).

19. The composition according to claim 18, wherein the chelating moiety comprises NOTA, NODASA or NODAGA.

20. The composition according to claim 19, wherein the chelating moiety comprises NODAGA.

21. The composition according to any one of claims 1-20, wherein *Cu is 61 Cu or 67 Cu.

22. The composition according to claim 21, wherein *Cu is 61 Cu.

23. The composition according to claim 21, wherein *Cu is 67 Cu.

24. The composition according to any one of claims 1-23, wherein the targeting moiety is recognized by a molecular target expressed at a site of tissue remodeling in malignant cells or pre-malignant cells, cells in the tumor microenvironment, inflamed tissue or a site of myocardial infarction or interstitial lung disease fibrosis.

25. The composition according to claim 24, wherein the molecular target is a tumor specific antigen (TSA).

26. The composition according to claim 24, wherein the molecular target is a tumor associated antigen (TAA).

27. The composition according to claim 24, wherein the targeting moiety comprises a urea-based prostate specific membrane antigen (PSMA) inhibitor.

28. The composition according to claim 27, wherein the targeting moiety comprises an L-lysine-urea-glutamic acid-based PSMA inhibitor.

29. The composition according to claim 28, wherein the targeting moiety comprises lysine-urea-glutamic acid (KuE).

30. The composition according to claim 24, wherein the targeting moiety comprises a peptide analogue of somatostatin.

31. The composition according to claim 24, wherein the targeting moiety comprises a cyclic octapeptide analogue of somatostatin.

32. The composition according to claim 24, wherein the targeting moiety comprises a fibroblast activation protein (FAP) inhibitor.

33. The composition according to claim 35, wherein the FAP inhibitor comprises (S)-6-amino-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide).

34. The composition according to claim 24, wherein the targeting moiety comprises D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr(ol).

35. The composition according to claim 24, wherein the targeting moiety comprises p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-aminophenyl(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH2.

36. The composition according to claim 24, wherein the targeting moiety comprises lysine-urea-glutamic acid (KuE), and L is suberic acid-D-lysine-D-phenylalanine-3-iodo-D-tyrosine (Sub-k-f-(I-y)) = 32-amino-29-benzyl-33-(4-hydroxy-3-iodophenyl)-5,13,20,28,31-pentaoxo-4,6,12,21,27,30-hexaaza-tritriacontane-1,3,7,26-tetracarboxylic acid.

37. The composition according to claim 24, which comprises a radiotracer having the following structure:

38. The composition according to claim 24, which comprises a radiotracer having the following structure:

39. The composition according to claim 24, which comprises a radiotracer having the following structure:

40. The composition according to claim 24, which comprises a radiotracer having the following structure:

41. The composition according to claim 24, which comprises a radiotracer having the following structure:

42. The composition according to claim 24, which comprises a radiotracer having the following structure:

43. The composition according to claim 24, which comprises a radiotracer having the following structure:

44. A method of generating an image of a subject, which comprises: Administering to the subject a composition according to any one of claims 1-21 and 24-43, wherein *Cu is 61 Cu; and Generating an image of at least a part of the body of the subject.

45. The method according to claim 44, wherein the image is generated using positron emission tomography (PET).

46. The method according to claim 45, wherein *Cu is 61 Cu.

47. The method according to claim 44, wherein the image is generated using single photon emission computed tomography (SPECT).

48. The method according to claim 47, wherein *Cu is 67 Cu.

49. A method of detecting a disease of a subject, which comprises: Administering to the subject a composition according to any one of claims 1-39, wherein *Cu is 61 Cu]Cu; and Detecting the localization of the radiotracer; and Determining the presence or absence of a disease based on the presence or absence of the localization of the radiotracer.

50. The method according to claim 49, wherein positron emission tomography (PET) is used to detect the localization of the radiotracer.

51. The method according to claim 50, wherein *Cu is 61 Cu.

52. The method according to claim 49, wherein single photon emission computed tomography (SPECT) is used to detect the localization of the radiotracer.

53. The method according to claim 52, wherein *Cu is 67 Cu.

54. The method according to any one of claims 49 - 53, wherein the disease is selected from cancer, inflammatory diseases, infectious diseases, and immune diseases.

55. The method according to claim 54, wherein the disease is selected from cancer, myocardial infarction, and interstitial lung disease, and the cancer is selected from tumors expressing somatostatin receptors such as neuroendocrine tumors, prostate cancer, and malignant meningioma, epithelial cancers overexpressing FAP and their respective microenvironments including non - small cell lung cancer, triple - negative breast cancer, colorectal cancer, gastric cancer, ovarian cancer, and pancreatic cancer.

56. The method according to claim 54, wherein the disease is cancer, and the cancer is selected from breast cancer (e.g., triple - negative breast cancer), pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer (e.g., non - small cell lung cancer), head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumors, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic cancer, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

57. The method according to claim 54, wherein the disease is selected from cardiovascular diseases, liver fibrosis and cirrhosis, arthritis diseases, IgG4 - related diseases, pulmonary fibrosis and interstitial lung disease, Crohn's disease, tuberculosis, sarcoidosis, and periprosthetic joint infection.

58. A method for monitoring or determining the effect of cancer treatment on a subject with cancer, comprising: Administering the composition according to any one of claims 1-39 to the subject at an earlier time point, where *Cu is 61 Cu; and at a later time point; Detecting the localization of the radiotracer at both the earlier time point and the later time point; And Monitoring or determining the effect of cancer treatment by comparing the amount of localization at the later time point with the amount of localization at the earlier time point.

59. The method according to claim 58, wherein positron emission tomography (PET) is used to detect the localization of the radiotracer. The method according to claim 59, wherein *Cu is 61 Cu.

61. The method according to claim 58, wherein single photon emission computed tomography (SPECT) is used to detect the localization of the radiotracer. The method according to claim 61, wherein *Cu is 67 Cu.

63. The method according to any one of claims 58 - 62, wherein the earlier time point is before the start of cancer treatment, and the later time point is at least one month after the start of cancer treatment.

64. The method according to claim 63, wherein the cancer is selected from tumors expressing somatostatin receptors such as neuroendocrine tumors, prostate cancer, and malignant meningioma; epithelial cancers overexpressing FAP and their respective microenvironments including non - small cell lung cancer, triple - negative breast cancer, colorectal cancer, gastric cancer, ovarian cancer, and pancreatic cancer.

65. The method according to claim 63, wherein the cancer is selected from breast cancer (e.g., triple-negative breast cancer), pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer), head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumors, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary origin), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

66. A method for generating an image of a subject, comprising: Administering to the subject a composition according to any one of claims 1-21 and 23-43, wherein *Cu is 67 Cu; and generating an image of at least a part of the body of the subject using single photon emission computed tomography (SPECT).

67. A method for monitoring the distribution and effect of cancer treatment on a cancer patient, comprising: Administering to the subject a composition according to any one of claims 1-21 and 23-43, wherein *Cu is 67 Cu; and detecting the localization of the radiotracer using SPECT.

68. A method of providing radionuclide therapy to a cancer patient in need thereof, comprising administering to said patient an effective amount of a composition according to any one of claims 1-21 and 23-43, wherein *Cu is 67 Cu.

69. A method of treating cancer in a patient in need thereof, comprising administering to said patient an effective amount of a composition according to any one of claims 1-21 and 23-43, wherein *Cu is 67 Cu.

70. The method according to claim 66 or 67, wherein the cancer is selected from tumors expressing somatostatin receptors such as neuroendocrine tumors, prostate cancer, and malignant meningioma; epithelial cancers overexpressing FAP and their respective microenvironments including non-small cell lung cancer, triple-negative breast cancer, colorectal cancer, gastric cancer, ovarian cancer, and pancreatic cancer.

71. The method according to claim 66 or 67, wherein the cancer is selected from breast cancer (e.g., triple-negative breast cancer), pancreatic cancer, small intestine cancer, colon cancer, gastric cancer, rectal cancer, lung cancer (e.g., non-small cell lung cancer), head and neck cancer, ovarian cancer, hepatocellular carcinoma, epithelial cancer, esophageal cancer, hypopharyngeal cancer, nasopharyngeal cancer, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, renal clear cell carcinoma, neuroendocrine tumors, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary origin), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

72. A method for manufacturing a pharmaceutical composition comprising any one of the substances according to claims 1-43.

73. A radiopharmaceutical composition comprising an active ingredient according to any one of claims 1-43.

74. The radiopharmaceutical composition according to claim 73, wherein the radiopharmaceutical composition comprises tools for generating images according to claims 44-48 and 66, tools for detecting diseases according to claims 49-57, tools for monitoring cancer treatment according to claims 58-65 and 67, or tools for treating cancer according to claims 68-71.

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