High purity copper radiopharmaceutical compositions and their diagnostic and therapeutic uses

Abstract

The present disclosure relates to the field of nuclear imaging and therapy, and more particularly to high-purity copper radiotracer compositions useful for imaging and therapy, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). More particularly, the present disclosure relates to novel compositions useful for imaging and therapy of conditions such as prostate cancer, somatostatin receptor-expressing tumors such as neuroendocrine tumors, epithelial tumors, and the like, and methods by which such compositions are prepared.

Description

[Technical Field]

[0001] 1. Background The present disclosure provides a novel, high-purity 6x This disclosure relates to a new class of radiotracers based on a Cu radionuclide generation platform that has the potential for "true theranostic" use, combining cancer diagnosis and treatment with a single chemical entity that meets the requirements of an ideal positron emission tomography (PET) or single-photon emission computed tomography (SPECT) tracer. More specifically, this disclosure relates to novel constructs and compositions thereof and their uses in the imaging, diagnosis, and treatment of conditions such as myocardial infarction, interstitial lung disease, and cancers, including prostate cancer, FAP-expressing epithelial tumors, and neuroendocrine tumors, as well as methods of making these compositions. [Background technology]

[0002] In nuclear medicine, radiotracers are used in the diagnosis and treatment of various conditions and diseases. A radiotracer is a compound in which a radionuclide is linked to a targeting moiety that targets specific organs, cells, or biomarkers in the human body.

[0003] Radiotracers involve the use of targeting moieties that selectively localize to malignant cells, tumors, or their associated microenvironment, and the use of low-range, highly ionizing radiation, e.g., α or β - With radionuclides selected to emit particles, they can be used in targeted radionuclide therapy. The combination of both disease diagnosis and treatment, utilizing the same or similar biological targeting moieties to target specific biomarkers (e.g., cell surface receptors) with different diagnostic and therapeutic radionuclides, is called targeted theranostics. This approach overcomes the difficulty of quantifying the individual doses required for treatment through diagnosis, allowing for highly personalized patient treatment. The theranostics approach utilizes isotopically distinct radiotracers that bind identically to biomarkers, and thus utilizes radionuclides of the same element, such as copper radionuclides as positron emitters in diagnostic imaging. 60 Cu,61 Cu, 62 Cu and 64 Cu as an electron emitter in radiation therapy 67 Further improvement is achieved using Cu.

[0004] The availability of a large portfolio of active, high-purity radiotracers is essential for the development of nuclear medicine. A variety of copper radionuclides are used in the field of nuclear medicine, offering diverse options for applications in radionuclide imaging (e.g., in radiotracers) and therapy.

[0005] 60 Cu, 61 Cu, 62 Cu, 64 Cu and 67 Copper radionuclides, including Cu, offer a variety of options for applications in imaging and therapy. 60 Cu(t 1 / 2 =23.4 minutes), 61 Cu(t 1 / 2 = 3.32 hours) and 62 Cu(t 1 / 2 = 9.76 min) is the electron capture and β + They decay by emission, and are converted to Cu-pyruvaldehyde bis(N 4 It has been used to prepare perfusion agents such as Cu-ethylglyoxal bis(thiosemicarbazone) (PTSM) and Cu-ethylglyoxal bis(thiosemicarbazone) ETS. 67 Cu(t 1 / 2 = 62.01 hours) is β - It decays only upon release and has been used to label monoclonal antibodies and antibody fragments for radioimmunotherapy. 64 Cu has an intermediate half-life of 12.7 hours and a unique decay profile (β + :18%, β - 38% and electron capture yield 44%), making it useful for radiolabeling of nanoparticles, antibodies, antibody fragments, peptides, and small molecules for PET imaging and radionuclide therapy. 64 Cu radiopharmaceuticals were used for quantitative PET imaging.64 Cu or its beta-emitting isotope 67 Radiation dosimetry can be calculated before administering targeted radiotherapy with Cu. 64 Cu has been incorporated into many labeled radiotracers based on antibodies, peptides and small molecules that target specific receptors or antigens, especially in oncology applications.

[0006] More recently, 61 Cu(t 1 / 2 =3.33 hours, 61%β + , Emax=1.216MeV) is 60 Cu and 62 Due to its longer half-life (3.33 hours) than Cu, it is considered a better option for long-term imaging of slow-reaction processes. 61 Cu is 68 Copper-60 and copper-61 are positron-emitting radionuclides that exhibit decay characteristics comparable to those of [Ga]Ga, but with the advantage of a lower maximum positron energy (Emax = 1.216 MeV vs. Emax = 1.899 MeV) and a substantially more practical half-life (3.33 hours vs. 68 minutes). (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 lower radiation doses to the patient.

[0007] Radionuclides can be used in personalized medicine, but supplying them in quantity and quality for clinical use is a challenge. It is important to produce target "coins" (often disk-shaped objects bearing target metals that are bombarded with subatomic particles to produce radionuclides) with the required radionuclide purity and that can produce radionuclide compositions that are active at the end of bombardment (EoB), end of synthesis (EoB+2 hours), or calibration. Preparation of suitable target coins is one of the most important aspects of cyclotron production of radionuclides.

[0008] Currently, PET is the only high-precision nuclear medicine imaging procedure that allows visualization and measurement of biochemical processes in cancer diagnosis. PET provides detailed information about disease progression that cannot be achieved through other imaging techniques or through more invasive procedures alone. While the effectiveness of radionuclides as PET tracers is clear, there are significant barriers to their widespread use, including 1) high manufacturing costs (>400 Euros or $400 / dose), 2) inflexible chemistry (requiring complex and expensive radiochemical infrastructure), 3) limited distribution radius (short half-life), and 4) high radiation burden that puts patients at risk.

[0009] US Patent Application Publication No. 2006 / 0004491 describes methods for preparing radiodiagnostic agents, such as for use in PET imaging. 60 Cu, 61 Cu and 64 A functional automated process for the separation and recovery of Cu usage is described.

[0010] US Patent No. 10,975,089 relates to compounds that are said to be useful as radiopharmaceuticals for use in radiotherapy and diagnostic imaging, such as radiocontrast agents with radionuclide chelators.More specifically, compounds are described that are said to exhibit improved binding affinity to PSMA.According to US Patent No. 10,975,089, the use of amino acid-substituted ureas linked to macrocyclic sarcofagin via specific linkers provides compounds that bind to PSMA and provide improved imaging properties when complexed with radionuclides.

[0011] It is an object of the present disclosure to provide compositions and methods that completely or partially overcome one or more of the problems identified in the prior art involving radiopharmaceuticals, such as radiotracers, and their preparation. Summary of the Invention

[0012] 2. Overview In a first aspect of the present disclosure, a chelating moiety and optionally a chelated copper radionuclide ( * Cu) and a targeting moiety covalently linked to a chelating moiety.

[0013] In certain embodiments, a compound is provided, wherein the compound is a compound of formula X: [ka] or a pharmaceutically acceptable salt thereof; [ka] is a chelating moiety, * Cu is optional and, if present, 61 Cu, 62 Cu, 64 Cu and 67 Cu, L is a bond or a linker moiety; V is a targeting moiety; n is an integer from 1 to 10, m is an integer from 1 to 10, p is an integer from 1 to 10.

[0014] In certain embodiments, a compound is provided, wherein the compound is a compound of formula A: [ka]

[0015] In certain embodiments of a compound of Formula X or Formula A, the chelating moiety comprises 2 to 8 binding moieties, in certain embodiments, one or more of the binding moieties is selected from a thiol group, an amine group, and a carboxylate group.

[0016] In certain embodiments, the chelating moiety comprises 2,2',2"-(1,4,7-triazonane-1,4,7-triyl)triacetic acid (NOTA); 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)succinic acid (NODASA); 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid (NODAGA); or 2,2'((2-(,7-bis-(carboxymethyl)-1,4,7-triazonan-1-yl)ethyl)azanediyl)diacetic acid (NETA).

[0017] In certain embodiments, the targeting moiety is recognized by a molecular target expressed by malignant or pre-malignant cells, cells in the tumor microenvironment, inflamed tissue, or sites of tissue remodeling in sites of fibrosis in myocardial infarction or interstitial lung disease.

[0018] In a second aspect of the present disclosure, there is provided a composition comprising a compound of Formula X or Formula A, or a pharmaceutically acceptable salt thereof. Preferably, the composition has a radiochemical purity of 91% or greater or a molar radioactivity of 1 to 250 MBq / nmol. In certain embodiments, the composition has both a radiochemical purity of 91% or greater and a molar radioactivity in the range of 1 to 250 MBq / nmol.

[0019] In the illustrated embodiment, compounds, e.g., novel 61 Cu radiotracers and compositions thereof are provided for (i) imaging, diagnosis, and staging of cancers such as prostate cancer, somatostatin receptor-expressing cancers, and epithelial cancers (e.g., 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 etc. 61 In further contemplated embodiments, (ii) targeted radionuclide therapy of cancers such as prostate cancer, somatostatin receptor-expressing cancers, and epithelial cancers (e.g., [Cu]Cu-based radiotracers). 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 67 (using a Cu-based radioactive tracer).

[0020] In a third aspect of the present disclosure, there is provided a method of generating an image of a subject, the method comprising administering to the subject a composition according to the first aspect of the present disclosure and generating an image of part or more 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 In certain embodiments, SPECT is used and *Cu is 67 It is Cu.

[0021] In a fourth aspect of the present disclosure, there is provided a method for detecting a disease in a subject, the method comprising administering to the subject a composition according to the first aspect of the present disclosure and detecting localization of the radiotracer in the subject, for example using PET or SPECT. In certain embodiments, PET is used, and *Cu is [ 61 In certain embodiments, SPECT is used and *Cu is 67 It is Cu.

[0022] In certain embodiments, the diseases detected include cancers, e.g., somatostatin receptor-expressing cancers such as neuroendocrine tumors, prostate cancer, and malignant meningiomas; FAP-overexpressing epithelial cancers and their respective microenvironments, 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.

[0023] In a fifth aspect of the present disclosure, there is provided a method of monitoring the effect of cancer treatment on a subject suffering from cancer, the method comprising administering to the subject a composition according to the first aspect of the present disclosure and detecting localization of the radiotracer within the subject, for example using PET or SPECT. In certain embodiments, PET is used, and *Cu is [ 61 In certain embodiments, SPECT is used and *Cu is 67 It is Cu.

[0024] In a sixth aspect of the present disclosure, there is provided a method of providing radionuclide therapy to a cancer 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 It is Cu.

[0025] 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 It is Cu.

[0026] 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 meningiomas; FAP-overexpressing epithelial cancers such as non-small cell lung cancer, triple-negative breast cancer, colorectal cancer, gastric cancer, ovarian cancer, and pancreatic cancer, and their respective microenvironments.

[0027] 3. Brief description of the drawings These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following description and accompanying drawings. [Brief explanation of the drawings]

[0028] [Figure 1] Increasing magnifications show a homogenous nickel coating with durable adhesion to the niobium coin upon completion of electroplating as assessed using a DINOLite digital microscope: Panel A, 20x magnification; Panel B, 50x magnification; Panel C, 250x magnification.

[0029] [Figure 2] 1 shows a sample coin provided in accordance with the present disclosure with nickel deposited in the center of a niobium backing.

[0030] [Figure 3] Analysis of the 61Cu purity of a [61Cu]CuCl2 solution obtained by irradiation of natNi on a Nb backing with an 8.4 MeV deuteron beam at 50 μA for 3 hours. The curve corresponds to the decrease in 61Cu purity % over time, and the bar graph corresponds to the radioactive cobalt activity over time.

[0031] [Figure 4] Analysis of the 61Cu purity of a [61Cu]CuCl2 solution obtained by irradiation of 60Ni on a Nb backing with an 8.4 MeV deuteron beam at 50 μA for 3 hours. The curve corresponds to the decrease in 61Cu purity % over time, and the bar graph corresponds to the radioactive cobalt activity over time.

[0032] [Figure 5] Figure 1 shows the radioactivity concentrations of detected impurities in [61Cu]CuCl solutions produced according to various methods. The (Ag, natNi) data was generated based on irradiation of a commercially available natNi target on an Ag backing. The (Nb, natNi) and (Nb,Ni-61) data were generated based on irradiation of a Ni target (natural and isotopically enriched in 61Ni, respectively) electroplated according to the present disclosure on a high-purity Nb backing. Radioactivity concentrations were assessed by gamma spectroscopy and reported in Bq / g. The data show that silver and cobalt isotopes are significantly depleted in [61Cu]CuCl solutions produced by irradiation of a Ni target electroplated according to the present disclosure on a high-purity Nb backing.

[0033] [Figure 6] Figure 1 illustrates a significant reduction in the total radionuclide impurities present in [61Cu]CuCl2 solutions produced according to various methods. The (Ag, natNi) data was generated based on irradiation of a commercially available natNi target on an Ag backing. The (Nb, natNi) and (Nb,Ni-61) data were generated based on irradiation of a Ni target (natural and isotopically enriched in 61Ni, respectively) electroplated according to the present disclosure on a high-purity Nb backing. Radionuclide impurities were determined by gamma spectroscopy and reported in Bq / g (total radionuclide impurities). The presented data particularly highlight the reduction in overall impurities in [61Cu]CuCl2 solutions when produced according to the present disclosure.

[0034] [Figure 7]Figure 1 illustrates the sustained high radionuclide purity of a [61Cu]CuCl solution produced in accordance with the present disclosure compared to a commercially available natNi target on an Ag backing (ext. coin (Ag, natNi)). The (Nb, natNi) and (Nb, Ni-61) coins were prepared by electrodeposition according to the present disclosure onto a high-purity Nb backing. Data was generated using gamma spectroscopy and reported in Bq / g, providing the total radionuclide purity at t = 0 and t = 12 hours. The presented data highlight the superior quality of the [61Cu]CuCl solution when produced by irradiation of a Ni target electroplated according to the present disclosure onto a high-purity Nb backing; the purity after 12 hours is still well above the purity limits set by the Pharmacopoeia for similar radionuclides for medical use.

[0035] [Figure 8] FIG. 10 shows chemical impurities measured by ICP-MS of [61Cu]CuCl2 solution as produced by bombardment of natNi vs. 61Ni as produced by irradiation of a Ni target electroplated according to the present disclosure on a high purity Nb backing.

[0036] [Figure 9A] FIG. 1 shows the measured affinity of each construct as exemplified by IC50 determinations of various constructs as described in Example 5. [Figure 9B] FIG. 1 shows the measured affinity of each construct as exemplified by IC50 determinations of various constructs as described in Example 5. [Figure 9C]Figure 1 shows the measured affinity of each construct, exemplified by IC50 determinations of various constructs as described in Example 5. Panel A shows that switching the chelator from DOTAGA (the reference construct used in the clinic, DOTAGA-PSMA-I&T) and DOTA (the reference construct used in the clinic, DOTA-TOC) to the chelator NODAGA (NODAGA-PSMA-I&T and NODAGA-TOC, respectively) between two natCu-complexed PSMA constructs and two natCu-complexed TOC somatostatin analogs does not interfere with the affinity of the natCu-complexed constructs for their molecular targets (PSMA and SST2, respectively). Panel C shows that complexation of Cu (or radiolabeling with 61Cu) does not interfere with the affinity of the NODAGA-LM3 construct for its molecular target (SST2), as suggested by the unchanged IC50 values ​​of NODAGA-LM3 and natCu-NODAGA-LM3.

[0037] [Figure 10] Panel A shows dynamic PET / CT scans of [61Cu]Cu-DOTAGA-PSMA-I&T in a PSMA-positive tumor-bearing mouse within 1 hour obtained according to Example 8, and Panel B shows dynamic PET / CT scans of [61Cu]Cu-NODAGA-PSMA-I&T in a PSMA-positive tumor-bearing mouse within 1 hour obtained according to Example 8 (L=liver; K=kidney; I=intestine; Bl=bladder; T=tumor; J=joint; SG=salivary gland).

[0038] [Figure 11] Panels A and B were obtained according to Example 8. Panel A shows PET / CT images of [Cu]Cu-NODAGA-PSMA-I&T and [Cu]Cu-DOTAGA-PSMA-I&T 1 and 4 hours after injection in a PSMA-positive tumor-bearing mouse. Panel B shows the time-activity curves of the tumor and kidney, with circles representing [Cu]Cu-NODAGA-PSMA-I&T and squares representing [Cu]Cu-DOTAGA-PSMA-I&T.

[0039] [Figure 12] Panel A shows the progression of biodistribution (1-4 hours) of differentially chelated Cu2+ ([61Cu]Cu-DOTAGA-PSMA-I&T), panel B shows the progression of biodistribution (1-4 hours) of differentially chelated [61Cu]Cu-NOTAGA-PSMA-I&T, and panel C shows the biodistribution of unchelated [61Cu]CuCl2.

[0040] [Figure 13] Panels A and B show dynamic PET / CT scans within 1 hour and static PET / CT scans at 4 hours after injection of [61Cu]Cu-DOTA-TOC in an SST2-positive tumor-bearing mouse obtained according to Example 8. Panels C and D show dynamic PET / CT scans within 1 hour and static PET / CT scans at 4 hours after injection of [61Cu]Cu-NODAGA-TOC in an SST2-positive tumor-bearing mouse obtained according to Example 8. Panels E and F show dynamic PET / CT scans within 1 hour and static PET / CT scans at 4 hours after injection of [61Cu]Cu-NODAGA-LM3 in an SST2-positive tumor-bearing mouse.

[0041] [Figure 14] Panels A-C were obtained according to Example 10, where Panel A shows PET / CT scans of [61Cu]Cu-NODAGA-PSMA-I&T in PSMA-positive tumor-bearing mice 1 hour after injection of the radiotracer alone or 1 hour after injection of the blocking agent 2-PMPA, Panel B shows PET / CT scans of [61Cu]Cu-DOTAGA-PSMA-I&T in PSMA-positive tumor-bearing mice 1 hour after injection of the radiotracer alone or 1 hour after injection of the blocking agent 2-PMPA, and Panel C shows PET / CT scans of [61Cu]CuCl2 at 1 hour.

[0042] [Figure 15]Panel A shows dynamic PET / CT scans of [61Cu]Cu-NODAGA-F1 in dual HT1080.hFAP and HT1080.wt tumor-bearing mice within 1 hour, and panel B shows dynamic PET / CT scans of [61Cu]Cu-NODAGA-F3 in dual HT1080.hFAP and HT1080.wt tumor-bearing mice within 1 hour.

[0043] [Figure 16] Panel A shows a static PET / CT scan of [61Cu]Cu-NODAGA-F1 in a mouse with a FAP-positive xenograft at 1 hour, panel B shows a static PET / CT scan of [61Cu]Cu-NODAGA-F1 in a mouse with a FAP-positive xenograft at 4 hours, panel C shows a static PET / CT scan of [61Cu]Cu-NODAGA-F3 in a mouse with a FAP-positive xenograft at 1 hour, and panel D shows a static PET / CT scan of [61Cu]Cu-NODAGA-F3 in a mouse with a FAP-positive xenograft at 4 hours.

[0044] [Figure 17] Partition coefficients (log D PB S / octanol, pH=7.4) of Cu- and Ga-labeled conjugates (from left to right): [Cu]Cu-NODAGA-F1, [Cu]Cu-NODAGA-F3, [Cu]Cu-NODAGA-F2, [Cu]Cu-NODAGA-F4, [Ga]Ga-FAPI-46, and [Cu]Cu-NODAGA-FAPI-46).

[0045] [Figure 18] FIG. 1 shows the inhibition (IC50) of [natCu]Cu-NODAGA-F1, [natCu]Cu-NODAGA-F3, [natCu]Cu-NODAGA-F2, and [natCu]Cu-NODAGA-F4.

[0046] [Figure 19]Panel A shows the cell surface cellular uptake (cell membrane-bound) and internalized fraction of [Cu]Cu-NODAGA-F1, panel B shows the cell surface cellular uptake (cell membrane-bound) and internalized fraction of [Cu]Cu-NODAGA-F3, panel C shows the cell surface cellular uptake (cell membrane-bound) and internalized fraction of [Cu]Cu-NODAGA-F2, and panel D shows the cell surface cellular uptake (cell membrane-bound) and internalized fraction of [Cu]Cu-NODAGA-F4. Values ​​are expressed as % of irradiated radioactivity and refer to 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 = total - nonspecific).

[0047] [Figure 20] Figure 1 shows the cell surface uptake (cell membrane-bound) and internalized fraction of [Cu]Cu-NODAGA-FAPI-46. Values ​​are expressed as % of delivered radioactivity and refer to 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 = total - nonspecific).

[0048] [Figure 21] Figure 1 shows saturable binding of [Cu]Cu-labeled conjugates, [Cu]Cu-NODAGA-F1, [Cu]Cu-NODAGA-F2, [Cu]Cu-NODAGA-F3, [Cu]Cu-NODAGA-F4, and [Cu]Cu-NODAGA-FAPI-46, on isolated HEK-293-hFAP membranes.

[0049] [Figure 22] Panel A shows the biodistribution profile of [61Cu]Cu-NODAGA-FAPI-46 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration, and panel B shows the biodistribution profile of [68Ga]Ga-FAPI-46 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration.

[0050] [Figure 23] Panel A shows the tumor-to-organ ratios of [61Cu]Cu-NODAGA-FAPI-46 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration, and panel B shows the tumor-to-organ ratios of [68Ga]Ga-FAPI-46 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration.

[0051] [Figure 24] Panel A shows the biodistribution profile of [61Cu]Cu-NODAGA-F1 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration, and panel B shows the biodistribution profile of [61Cu]Cu-NODAGA-F3 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration.

[0052] [Figure 25] Panel A shows the biodistribution profile of [61Cu]Cu-NODAGA-F2 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration, and panel B shows the biodistribution profile of [61Cu]Cu-NODAGA-F4 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration.

[0053] [Figure 26] Panel A shows the tumor-to-organ ratios of [61Cu]Cu-NODAGA-F1 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration, and panel B shows the tumor-to-organ ratios of [61Cu]Cu-NODAGA-F3 in HT-1080.hFAP tumor-bearing mice 1 and 4 hours after administration.

[0054] [Figure 27]Panel A shows the tumor-to-organ ratios of [61Cu]Cu-NODAGA-F2 in HT-1080.hFAP tumor-bearing mice 1 and 3 hours after administration, and panel B shows the tumor-to-organ ratios of [61Cu]Cu-NODAGA-F4 in HT-1080.hFAP tumor-bearing mice 1 and 3 hours after administration.

[0055] [Figure 28] Panel A shows a dynamic PET / CT scan of [61Cu]Cu-NODAGA-F2 in a mouse bearing a FAP-positive xenograft, and panel B shows a dynamic PET / CT scan of [61Cu]Cu-NODAGA-F4 in a mouse bearing a FAP-positive xenograft.

[0056] [Figure 29] Panel A shows a dynamic PET / CT scan of [61Cu]Cu-NODAGA-FAPI-46 in a mouse bearing a FAP-positive xenograft, and panel B shows a dynamic PET / CT scan of [68Ga]Ga-FAPI-46 in a mouse bearing a FAP-positive xenograft.

[0057] [Figure 30] Panel A shows SUV PET imaging of [61Cu]Cu-NODAGA-F2 vs. [61Cu]Cu-NODAGA-F4 (1 hour and 4 hours), and panel B shows SUV PET imaging of [61Cu]Cu-NODAGA-FAPI-46 vs. 68Ga-FAPI-46 ([61Cu]Cu-NODAGA-FAPI-46 at 1 hour and 4 hours, 68Ga-FAPI-46 at 1 hour only).

[0058] [Figure 31] 1 shows the distribution of [61Cu]Cu-NODAGA-PSMA-I&T (1 hour and 4 hours) versus [68Ga]Ga-PSMA-11 (1 hour) in a mouse model.

[0059] [Figure 32A]1 provides 1H-NMR data for NODAGA-PSMA-I&T. FIG. 2 shows the 1H-NMR spectrum. [Figure 32B] 1 provides 1H-NMR data for NODAGA-PSMA-I&T. 2 shows chemical shifts and fragments associated with each residue of NODAGA-PSMA-I&T. [Figure 32C] 1 provides 1H-NMR data for NODAGA-PSMA-I&T. 2 shows chemical shifts and fragments associated with each residue of NODAGA-PSMA-I&T.

[0060] [Figure 33] [61Cu]Cu-NODAGA-LM3 distribution after 1 and 4 hours (imaged by PET / CT) versus [68Ga]Ga-DOTA-TOC distribution after 1 hour (imaged by PET).

[0061] [Figure 34] 1 shows the distribution of [61Cu]Cu-NODAGA-LM3 versus [68Ga]Ga-DOTA-TOC compounds in several organs after 1 hour.

[0062] [Figure 35] Panels A–E show PET / CT images and planar scintigraphy of a 48-year-old patient with metastatic castration-resistant prostate cancer whose disease progressed after abiraterone and docetaxel treatment and who is scheduled to receive [61Cu]Cu-NODAGA-PSMA-I&T treatment. The patient also underwent left nephrectomy. The maximum intensity projection image (Panel A) shows strong tracer uptake by multiple bone, pelvic lymph node, and liver metastases. PET (Panel B), fused PET and CT (Panel B), and CT (Panel C) of an axial transverse section through the liver show two PSMA-positive liver lesions with focal tracer uptake. Non-contrast-enhanced CT image (Panel D). Planar anterior and post-treatment images 24 hours after administration of [177Lu]Lu-PSMA-I&T show radioactivity distribution similar to the PET image (Panel E).

[0063] [Figure 36] Panel A shows a dynamic PET / CT scan of [61Cu]Cu-(R)-NODAGA-LM3 in a mouse bearing an SST2-positive xenograft, and panel B shows a dynamic PET / CT scan of [61Cu]Cu-NODAGA-LM3 in a mouse bearing an SST2-positive xenograft. Static images at 240 minutes are also presented.

[0064] [Figure 37] Figure 1 shows the saturation binding of [Cu]Cu-NODAGA-LM3. The Bmax ranges from 0.2082 nM to 0.2711 nM, and the kD ranges from 1.409 nM to 2.917 nM. DETAILED DESCRIPTION OF THE INVENTION

[0065] 4. Detailed Description 4.1.Definition When describing embodiments of the present disclosure, including compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated:

[0066] Generally, terms used in this specification, and particularly in the appended claims (e.g., the body of the appended claims), are generally intended as "non-limiting" terms (e.g., the term "including" should be interpreted as "including, but not limited to," the term "having" should be interpreted as "having at least," and the term "includes" should be interpreted as "including, but not limited to"). Where a specific number of introduced claim recitations are intended, such intention will be explicitly set forth in the claim; in the absence of such recitation, it will be further understood by those skilled in the art that no such intention exists. For example, to aid in understanding, the following appended claims may include the use of the introductory phrases "at least one" and "one or more" to introduce the claim recitations. However, the use of such phrases should not be interpreted as meaning that the introduction of a claim recitation with the indefinite article "a" or "an" limits any particular claim that includes such an introduced claim recitation to embodiments that include only one such recitation, even if the same claim includes the introductory phrase "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be interpreted to mean "at least one" or "one or more"). The same applies to the use of definite articles used to introduce claim recitations. Moreover, even when a specific number of introduced claim recitations is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., a plain recitation of "two recitations" without any other modifiers means at least two recitations, or more than two recitations).Furthermore, when a convention similar to "at least one of A, B, and C, etc." is used, generally such a configuration is intended in the sense that one of ordinary skill in the art would understand the convention (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, systems having A only, B only, C only, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). When a convention similar to "at least one of A, B, or C, etc." is used, generally such a configuration is intended in the sense that one of ordinary skill in the art would understand the convention (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, systems having A only, B only, C only, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those skilled in the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the specification, claims, or drawings, should be understood to contemplate the possibility of including one of the terms, either of the terms, or both terms. For example, the phrase "A or B" is understood to include the possibilities of "A or B" or "A and B."

[0067] Additionally, where features or aspects of the present disclosure are described in terms of a Markush group, one of skill in the art will recognize that the present disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0068] As will be understood by those skilled in the art, for any and all purposes, e.g., with respect to providing a written description, all ranges recited herein also encompass any and all possible subranges and combinations of subranges. A recited range can be readily recognized as fully descriptive and allows for the same range to be divided into at least two, three, four, five, ten, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third, and upper third, etc. As will also be understood by those skilled in the art, all language, such as "up to," "at least," "greater than," and "less than," refers to a range that is inclusive of the recited numbers and can subsequently be broken down into subranges as discussed above. Finally, as will be understood by those skilled in the art, a range includes individual members. Thus, for example, a group having 1 to 3 items refers to a group having 1, 2, or 3 items. Similarly, a group having 1 to 5 items refers to a group having 1, 2, 3, 4, or 5 items, etc.

[0069] As used herein, the term "alkyl" refers to straight and branched chain C-C alkyl groups. 30 It refers to both saturated and unsaturated hydrocarbons, e.g., "C1-C 20 Use of a designation such as " is intended to refer to an alkyl (e.g., straight or branched chain, including alkenes and alkyls) having the recited range of carbon atoms. In certain embodiments, an alkyl group has 1 to 10 carbon atoms ("C1-C 10In certain embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-C9 alkyl"). In certain embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In certain embodiments, an alkyl group has 1 to 7 carbon atoms ("C1-C7 alkyl"). In certain embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In certain embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"). In certain embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl"). In certain embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-C3 alkyl"). In certain embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-C2 alkyl"). In certain embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). Examples of C1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, and the like. Representative straight-chain alkyls include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, etc., while saturated branched alkyls include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, etc. Representative saturated cyclic alkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0070] As used herein, the term "alkenyl" refers to the radical of a straight-chain or branched hydrocarbon 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) ("C-C 20 In certain embodiments, an alkenyl group does not contain any triple bonds. In certain embodiments, an alkenyl group has 2 to 10 carbon atoms ("C-C 10In certain embodiments, an alkenyl group has from 2 to 9 carbon atoms ("C2-C9 alkenyl"). In certain embodiments, an alkenyl group has from 2 to 8 carbon atoms ("C2-C8 alkenyl"). In certain embodiments, an alkenyl group has from 2 to 7 carbon atoms ("C2-C7 alkenyl"). In certain embodiments, an alkenyl group has from 2 to 6 carbon atoms ("C2-C6 alkenyl"). In certain embodiments, an alkenyl group has from 2 to 5 carbon atoms ("C2-C5 alkenyl"). In certain embodiments, an alkenyl group has from 2 to 4 carbon atoms ("C2-C4 alkenyl"). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-C3 alkenyl"). In certain embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like.

[0071] As used herein, the terms "alkylene," "alkenylene," and "alkynylene" refer to a divalent radical of an alkyl, alkenyl, or alkynyl group, respectively. When a range or number of carbons is provided for a particular "alkylene," "alkenylene," or "alkynylene," it is understood that the range or number refers to the range or number of carbons in a linear, divalent carbon chain. "Alkylene," "alkenylene," and "alkynylene" groups can be substituted or unsubstituted with one or more substituents described herein.

[0072] As used herein, the term "aryl" refers to aromatic groups containing 6 to 10 carbons in the ring portion (e.g., monocyclic, bicyclic, and tricyclic structures). Aryl groups may be optionally substituted through available carbon atoms and, in certain embodiments, may contain one or more heteroatoms such as oxygen, nitrogen, or sulfur. In some embodiments, an aryl group has 6 ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; for example, naphthyl such as 1-naphthyl and 2-naphthyl).

[0073] As used herein, "halo" and "halogen" refer to an atom selected from fluorine (fluoro, F), chlorine (chloro, Cl), bromine (bromo, Br), and iodine (iodo, I).

[0074] As used herein, "heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 electrons shared within the cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided to the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems can 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 carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring; in such cases, the number of ring members continues to designate 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, and the point of attachment is on either the aryl or heteroaryl ring; in such cases, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl).

[0075] As used herein, the term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be a carbon atom or a nitrogen atom, valence permitting. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, and the point of attachment is on either the carbocyclyl or the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, and the point of attachment is on the heterocyclyl ring, in which case the number of ring members continues to specify the number of ring members in the heterocyclyl ring system. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic group" may be used interchangeably. Heterocycles include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0076] As used herein, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen present on the group (e.g., a hydrogen bonded to a carbon or nitrogen atom of the group) is replaced with an acceptable substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, 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 substituent may be the same or different at each position.

[0077] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C1-C6 alkyl" is intended to include 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 alkyl.

[0078] In typical embodiments, the present disclosure is intended to encompass the compounds disclosed herein, as well as pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomers, 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, tautomers, polymorphs, enantiomers, mixtures of enantiomers, stereoisomers, or mixtures of stereoisomers (pure or as racemic or non-racemic mixtures) of the compounds described herein.

[0079] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts. Alternatively, preferred isomers can be prepared by asymmetric synthesis. See, for example, 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, NY, 1962); and Wilen, "Tables of Resolving Agents and Optical Resolutions," p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers or as mixtures of various isomers.

[0080] With respect to chemical structures involving chelated metals, the depicted structures are not intended to define the coordination sphere. Furthermore, the presence or absence of a proton on the ionizable binding moiety is not intended to be determinative. One skilled in the art can determine the coordination sphere, oxidation state, and degree of ionization, as the case may be.

[0081] 4.2. Compounds One aspect of the present disclosure is the provision of compounds comprising one or more chelating moieties and one or more targeting moieties covalently attached via a bond or a bivalent or polyvalent linker moiety, L, which is optionally a copper radionuclide (*Cu). In embodiments comprising a copper radionuclide, the compounds are considered "radiolabeled" for use in diagnostic and / or therapeutic applications. These compounds are also referred to herein as "targeted chelator constructs" and are precursors to radiolabeled compounds, also referred to as "radiotracers." As used herein, certain compounds, e.g., radiotracers, are defined as compounds that contain a particular radioisotope or radionuclide (e.g., 61 When described herein as containing Cu), it is understood that the compound is isotopically enriched with that isotope at the indicated position.

[0082] The terms radioactive copper (also referred to herein as Cu*), copper radionuclide and copper radionuclide are used interchangeably herein and refer to isotopes of copper that undergo spontaneous radioactive decay.

[0083] An embodiment of the compounds of the present disclosure is 60 Cu, 61 Cu, 62 Cu, 64 Cu and 67 In certain embodiments, the radioactive copper is selected from: 61 Cu, 64 Cu and 67 In certain embodiments, the radioactive copper is selected from [ 61 In certain embodiments, the radioactive copper is 67 It is Cu.

[0084] Certain embodiments of the radiotracer of the present disclosure include radioactive copper (Cu*), where *Cu is in the (II) oxidation state.

[0085] In embodiments of the present disclosure, provided compounds comprise one or more chelating moieties and one or more targeting moieties covalently attached to the one or more chelating moieties via a bond or a bivalent or polyvalent linker moiety, L, which is optionally a copper radionuclide (*Cu).

[0086] In certain embodiments, a compound is provided, wherein the compound is a compound of formula X: [ka] or a pharmaceutically acceptable salt thereof; [ka] is a chelating moiety, L is a bond or linker moiety connecting the chelating moiety to the targeting moiety; V is a targeting moiety; n is an integer selected from 1 to 10; m is an integer selected from 1 to 10; p is an integer selected from 1 to 10.

[0087] In certain embodiments, a compound of formula X*: [ka] or a pharmaceutically acceptable salt thereof, [ka] is a chelating moiety, *Cu is 61 Cu, 62 Cu, 64 Cu and 67 Cu, L is a bond or linker moiety connecting the chelating moiety to the targeting moiety; V is a targeting moiety; n is an integer selected from 1 to 10; m is an integer selected from 1 to 10; p is an integer selected from 1 to 10.

[0088] In certain embodiments of a 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.

[0089] In certain embodiments of a 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.

[0090] In certain embodiments of compounds of Formula X, n is 1, m is 2, and p is 2, such that the chelating moiety is multivalent, with two L moieties linking two V targeting moieties to a bivalent chelator. In certain embodiments of compounds of Formula X, n is 1, m is 3, and p is 3, such that the chelating moiety is multivalent, with three L moieties linking three V targeting moieties to a trivalent chelator. In certain embodiments, each of the L moieties 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.

[0091] In certain embodiments of a compound of Formula X, n is 1, m and p are each the same integer and greater than 1, e.g., an integer from 2 to 10, and the chelating moiety is multivalent. 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.

[0092] In certain embodiments of a compound of Formula X (it is understood herein that Formula X encompasses the subgenus of Formula X1), n ​​is 1, m is 1, p is 1, and L is bivalent and links a chelating moiety to a targeting moiety. In certain embodiments where n is greater than 1, e.g., an integer from 2 to 10, L is multivalent and links one or more chelating moieties to a targeting moiety. In certain embodiments where n is 1, m is 2, and p is 2, the chelating moiety is multivalent (e.g., bivalent), and two linker moieties (L) each link two targeting moieties (V) to a bivalent chelator. In certain embodiments where n is 1, m is 3, and p is 3, the chelating moiety is multivalent, and three linker moieties (L) each link three targeting moieties (V) to a trivalent chelator. In certain embodiments, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, m is an integer of 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 of 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 of 3 to 5, 3 to 7, 5 to 7, 5 to 10, or 7 to 10.

[0093] In certain embodiments of compounds of formula X, n is 1, m is 2, p is 2, and each L is bivalent, linking each of two targeting moieties to a chelating moiety. In certain embodiments, n is 1, m is 1, p is 3, and L is multivalent, linking three of the targeting moieties (V) to a chelating moiety. In certain embodiments, n is 1, m is 1, p is 4, and L is multivalent, linking each of four targeting moieties to a chelating moiety.

[0094] In certain embodiments, the radioactive copper is 61 Cu, 64 Cu and 67 Cu, especially 61 Cu or 67 Cu.

[0095] Some embodiments of the radiotracer of the present disclosure include radioactive copper (Cu*), where *Cu is in the (II) oxidation state.

[0096] In certain embodiments, the compound is according to Formula A: [ka] or a pharmaceutically acceptable salt thereof; [ka] is a chelating moiety, L is a bond or linker moiety connecting the chelating moiety to the targeting moiety; V is a targeting moiety; n is an integer selected from 1 to 10.

[0097] In certain embodiments, the compound is according to formula A*: [ka] or a pharmaceutically acceptable salt thereof; [ka] is a chelating moiety, *Cu is optional and if present, 61 Cu, 62 Cu, 64 Cu or 67 Cu, L is a bond or linker moiety connecting the chelating moiety to the targeting moiety; V is a targeting moiety; n is an integer selected from 1 to 10.

[0098] In certain embodiments of 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 certain embodiments, n is 4.

[0099] 4.2.1. Chelating Moieties A chelating moiety comprises two or more binding moieties available to form several bonds with a single metal ion. [ka] where the line indicates the point of attachment) is not particularly limited.

[0100] In certain embodiments of compounds of formulas X, X*, A, and A*, the chelating moiety is selected from any known copper chelator known in the art. In certain embodiments, the chelating moiety is capable of complexing Cu(II) with a relatively fast coordination rate, high biological stability, and inertness. Known chelating moieties may 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.

[0101] In embodiments of the present disclosure, the term chelating moiety generally encompasses both coordinated and uncoordinated states. That is, a chelating moiety may be chelated to a metal, e.g., considered to be coordinated to a copper radionuclide, or may not be chelated to a metal, e.g., a copper radionuclide, and considered to be uncoordinated. In certain embodiments, when a chelating moiety is coordinated to radioactive copper, the term "chelated copper complex" is used herein.

[0102] In certain embodiments of compounds of formula X, X*, A, and A*, the chelating moiety comprises a binding moiety, i.e., a chemical group that contributes to binding of a metal ion to form a coordination complex (e.g., 1 to 10 atoms, e.g., 3 atoms, of a carboxylic acid group). In some examples, the binding moiety is capable of ionic, dative, and / or coordinate bonding. In certain embodiments, the chelating moiety comprises 2 to 8 binding moieties. In certain embodiments, the chelating moiety comprises 4, 5, 6, 7, or 8 binding moieties. In certain embodiments, the chelating moiety comprises 6 binding moieties.

[0103] In certain embodiments of compounds of formula X, X*, A, and A*, the binding moieties are selected from thiol groups, amine groups, and carboxylate groups. In certain embodiments, one or more binding moieties comprise a tertiary amine. In further of these embodiments, three or more binding moieties comprise a tertiary amine, for example, three tertiary amines form a cyclic ring around the metal center.

[0104] In certain embodiments of compounds of formula X, X*, A or A* of compounds of formula X or A, the chelating moiety is selected from the group consisting of DOTAGA (1,4,7,10-tetraazacyclododecane, 1-(glutaric 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-cyclododec-1-yl-acetic acid)), 3p-C-DEPA (2-[(carboxymethyl)][5-(4-nitrophenyl)-1-[4,7,10-tris(carbo 2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmethyl)-cyclododecane), oxo-DO3A (1-oxa-4,7,10-triazacyclododecane-5-S-(4-isothiocyanatobenzyl)-4,7,10-triacetic acid), TCMC (2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmethyl)-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), NOD A (1,4,7-triazacyclononane-1,4-diacetate), NODAGA (1,4,7-triazacyclononane-1-glutaric-4,7-acetic acid) (also known as NOTAGA), NODA desferoxamine (1,4,7-triazacyclononane-1,4-diyl)diacetic acid (DFO), NETA ([4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-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-hexazabicyclo(6,6,6)eicosane, 3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosane-1,8-diamine), Sarar (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexaazabicyclo[6.6.6]eicosane-1,8-diamine), The benzoic acid is selected from the group consisting of 4,4'-((3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosan-1,8-diamine), AmBaSar (4-((8-amino-3,6,10,13,16,19-hexazabicyclo[6.6.6]icosan-1-ylamino)methyl)benzoic acid) and 4,4'-((3,6,10,13,16,19-hexazabicyclo[6.6.6]ico-san-1,8-diylbis(aza-nediyl))bis(methylene))dibenzoic acid (BaBaSar).

[0105] In certain embodiments of compounds of Formulas X, X*, A and A*, the chelating moiety is selected from DOTAGA, DOTA, NOTA, NODAGA and NODA.

[0106] In certain embodiments of compounds of formula X, X*, A, and A*, the chelating moiety is NODAGA. In certain embodiments of compounds of formula A, the chelating moiety is R-NODAGA. In certain embodiments of compounds of formula X or A, the chelating moiety is NODAGA.

[0107] In further embodiments of the compounds of formulas X, X*, A, and A*, the chelating moiety comprises a structure selected from those shown below, and it should be noted that these structures may be considered to further comprise a linker moiety. There is some flexibility as to which atoms comprise the chelating moiety and which atoms comprise the linker used to connect the chelating moiety to one or more targeting ligands. For example, the chelating moiety in this embodiment shown below may comprise a complete amide group (-(C=O)NH-), or may comprise only a carbonyl -(C=O)-, and if -NH- is present, it is considered to be part of the linker group: [ka] [ka] [ka]

[0108] In certain embodiments of compounds of Formulas X, X*, A, and A*, the chelating moiety comprises 2,2',2"-(1,4,7-triazonane-1,4,7-triyl)triacetic acid (NOTA); 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)succinic acid (NODASA); 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid (NODAGA); or 2,2'((2-(,7-bis-(carboxymethyl)-1,4,7-triazonan-1-yl)ethyl)azanediyl)diacetic acid (NETA). In certain embodiments, the chelating moiety comprises derivatives of these moieties, such as functional derivatives and derivatives to which a linker moiety can be covalently attached.

[0109] In certain embodiments of compounds of formula 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.

[0110] In certain embodiments of compounds of Formulas 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 HDEDPA, as shown below. In certain embodiments, the chelating moiety comprises derivatives of these moieties, such as functional derivatives and derivatives to which a linker moiety can be covalently attached. [ka]

[0111] In certain embodiments of the compounds of formula X, X*, A, and A*, the chelating moiety comprises DOTA. In another particular embodiment, the chelating moiety comprises DOTAGA. In certain embodiments, the chelating moiety includes derivatives of these moieties, such as functional derivatives and derivatives to which a linker moiety can be covalently attached.

[0112] In certain embodiments of the compounds of formulas X, X*, A and A*, the chelating moiety is selected from the structure of NOTA, NODAGA, NODASA, DOTA, DOTAGA or DOTASA, for example, from those shown in the table immediately below, and a single attachment point to the targeting moiety is optionally indicated via a linker moiety.Each of the chelating moieties shown is also contemplated as being further modified to be a bivalent or polyvalent chelating moiety.In certain embodiments, one or more available carboxylate carbonyl carbons are attachment points (optionally via a linker moiety) with a second targeting moiety and optionally a third targeting moiety, thus replacing the hydroxyl group.In certain embodiments, a methylene carbon is attachment point (optionally via a linker moiety) for a second and optionally a third targeting moiety. [Table 1-1] [Table 1-2]

[0113] In certain embodiments of compounds of formula X, X*, A, and A*, the chelating moiety comprises a structure according to Formula 1: [ka] R 1 ,R 2 and R 3 are individually C 2-6 alkyl, optionally oxo, thiol, hydroxyl, C, including their deprotonated variants upon chelation with *Cu 1-3 Alkoxy, C1-3 Carboxy, and C 1-3 substituted with one or more substituents selected from alkylthiols; R 1 ,R 2 and R 3 One or more of comprises a point of attachment to a linker moiety (when L is a linker moiety) or a targeting moiety (when L is a bond).

[0114] In certain embodiments of compounds of formula X, X*, A and A*, the chelating moiety comprises a structure according to formula 1′: [ka] R 1 ,R 2 and R 3 are individually C 2-6 alkyl, optionally oxo, thiol, hydroxyl, C, including their deprotonated variants upon chelation with *Cu 1-3 Alkoxy, C 1-3 Carboxy, and C 1-3 substituted with one or more substituents selected from alkylthiols; [ka] represents the point of attachment to the linker moiety (when L is a linker moiety) or the targeting moiety (when L is a bond).

[0115] In certain embodiments of compounds of formula X, X*, A and A*, the chelating moiety comprises a structure according to formula 1'a. [ka]

[0116] In certain embodiments of compounds of formula X, X*, A, and A*, the chelating moiety comprises a structure according to Formula 2: [ka] X 1 ,X 2 and X 3 are individually selected from -OH, -NH2 and -SH, including their deprotonated variants upon chelation with *Cu; any methylene is optionally substituted with oxo, thiol, or hydroxyl; [ka] represents the point of attachment to the linker moiety (when L is a linker moiety) or the targeting moiety (when L is a bond).

[0117] In certain embodiments of compounds of formula X, X*, A and A*, the chelating moiety comprises a structure according to formula 2′: [ka] X 1 ,X 2 and X 3 are individually selected from -OH, -NH2 and -SH, including their deprotonated variants upon chelation with *Cu; any methylene is optionally substituted with oxo, thiol, or hydroxyl; [ka] represents the point of attachment to the linker moiety (when L is a linker moiety) or the targeting moiety (when L is a bond).

[0118] In certain embodiments of compounds of formula X, X*, A, and A*, the chelating moiety comprises a structure according to formula 2i, 2'i, 2ii, or 2iii: [ka] [ka] [ka] [ka]

[0119] In certain embodiments of compounds of formula X, X*, A and A*, the chelating moiety comprises a structure according to formula 2iR, 2'iR or 2iiR: [ka]

[0120] In certain embodiments of compounds of formula X, X*, A, and A*, the chelating moiety comprises a structure according to formula 3: [ka] R 1 ,R 2 ,R 3 and R 4 are individually C 2-6 alkyl, optionally oxo, thiol, hydroxyl, C, including their deprotonated variants upon chelation with *Cu 1-3 Alkoxy, C 1-3 Carboxy, and C 1-3 substituted with one or more substituents selected from alkylthiols; R 1 ,R 2 ,R 3 and R 4 One or more of comprises a point of attachment to a linker moiety (when L is a linker moiety) or a targeting moiety (when L is a bond).

[0121] In certain embodiments of compounds of formula X, X*, A and A*, the chelating moiety comprises a structure according to formula 3′: [ka] R 1 ,R2 ,R 3 and R 4 are individually C 2-6 alkyl, optionally oxo, thiol, hydroxyl, C, including their deprotonated variants upon chelation with *Cu 1-3 Alkoxy, C 1-3 Carboxy, and C 1-3 substituted with one or more substituents selected from alkylthiols; [ka] represents the point of attachment to the linker moiety (when L is a linker moiety) or the targeting moiety (when L is a bond).

[0122] In certain embodiments of compounds of formula X, X*, A, and A*, the chelating moiety comprises a structure according to Formula 2: [ka] X 1 ,X 2 ,X 3 and X 4 are individually selected from -OH, -NH2 and -SH, including their deprotonated variants upon chelation with *Cu; any methylene is optionally substituted with oxo, thiol, or hydroxyl; [ka] represents the point of attachment to the linker moiety (when L is a linker moiety) or the targeting moiety (when L is a bond).

[0123] In certain embodiments of compounds of formula X, X*, A and A*, the chelating moiety comprises a structure according to formula 4′: [ka] X 1 ,X 2,X 3 and X 4 are individually selected from -OH, -NH2 and -SH, including their deprotonated variants upon chelation with *Cu; any methylene is optionally substituted with oxo, thiol, or hydroxyl; [ka] represents the point of attachment to the linker moiety (when L is a linker moiety) or the targeting moiety (when L is a bond).

[0124] In certain embodiments of compounds of formula X, X*, A, and A*, the chelating moiety comprises a structure according to formula 4i, 4'i, or 4ii: [ka] [ka] [ka]

[0125] In certain embodiments of compounds of formula X, X*, A and A*, the chelating moiety comprises a structure according to formula 4iR or 4iiR. [ka]

[0126] In various embodiments of the chelating moieties described herein as Formulas 1-4, including all enumerated subgenera, the chelating moiety further comprises one or more selected from methylene (-CH-) and carbonyl (-C(=O)-). In certain embodiments, the chelating moiety further comprises one methylene and one carbonyl, e.g., -CH-C(=O)-.

[0127] Also contemplated are embodiments of the chelating moieties described herein as Formulas 1-4, including all enumerated subgenera, where each chelating moiety shown is further modified to be a bivalent or polyvalent chelating moiety. In certain embodiments, one or more available carboxylate carbonyl carbons are points of attachment to a second targeting moiety and optionally a third targeting moiety (optionally via a linker moiety), thus replacing a hydroxyl group. In certain embodiments, a methylene carbon is a point of attachment for a second and optionally a third targeting moiety (optionally via a linker moiety).

[0128] 4.2.2. Chelating Moieties In certain embodiments of compounds of formulas X* and A*, the compounds of the present disclosure comprise a chelating moiety chelated to a radionuclide, such as radioactive copper, i.e., the chelating moiety further comprises a radionuclide metal, or alternatively, the chelating moiety is complexed to a radionuclide metal center. In the embodiments provided below, bonds shown as lines between the binding moiety and the metal center are provided for illustrative purposes only, as these interactions are dynamic and environment-dependent.

[0129] In certain embodiments of the compounds of formula X* and A*, the chelated copper complex, i.e., the chelated copper complex comprising a chelating moiety and a copper radionuclide, comprises a structure according to formula I: [ka] R 1 ,R 2 and R 3 are individually C 2-6 alkyl, optionally oxo, thiol, hydroxyl, C, including their deprotonated variants upon chelation with *Cu 1-3 Alkoxy, C 1-3 Carboxy, and C 1-3 substituted with one or more substituents selected from alkylthiols; R 1 ,R 2 and R 3One or more of comprises a point of attachment to a linker moiety (when L is a linker moiety) or a targeting moiety (when L is a bond).

[0130] In certain embodiments of compounds of formula X* and A*, the chelated copper complex comprises a structure according to formula I': [ka] R 1 ,R 2 and R 3 are individually C 2-6 alkyl, optionally oxo, thiol, hydroxyl, C, including their deprotonated variants upon chelation with *Cu 1-3 Alkoxy, C 1-3 Carboxy, and C 1-3 substituted with one or more substituents selected from alkylthiols; [ka] represents the point of attachment to the linker moiety (when L is a linker moiety) or the targeting moiety (when L is a bond).

[0131] In certain embodiments of compounds of formula X* and A*, the chelated copper complex comprises a structure according to formula II: [ka] X 1 ,X 2 and X 3 are individually selected from -OH, -NH2 and -SH, including their deprotonated variants upon chelation with *Cu; any methylene is optionally substituted with oxo, thiol, or hydroxyl; [ka] represents the point of attachment to the linker moiety (when L is a linker moiety) or the targeting moiety (when L is a bond).

[0132] In certain embodiments of compounds of formula X* and A*, the chelated copper complex comprises a structure according to formula II': [ka] X 1 ,X 2 and X 3 are individually selected from -OH, -NH2 and -SH, including their deprotonated variants upon chelation with *Cu; any methylene is optionally substituted with oxo, thiol, or hydroxyl; [ka] represents the point of attachment to the linker moiety (when L is a linker moiety) or the targeting moiety (when L is a bond).

[0133] In certain embodiments of compounds of formula X* and A*, the chelated copper complex comprises a structure according to formula IIi, II'i, IIii, or IIiii: [ka] [ka] [ka] [ka]

[0134] 4.2.3. Linker part In certain embodiments of the compounds of formulas X, X*, A, and A*, the linker moiety (L) is a bond or a single-atom or multi-atom bond between the chelating moiety and the targeting moiety. Alternatively, the linker moiety is not particularly limited and can be any linker known in the field of bioconjugation, including linkers known in the construction of antibody-drug conjugates. The linker moiety can be selected according to the ease of synthesis, the instability of the linker moiety, the solubility of the radioactive tracer, and other considerations.

[0135] In certain embodiments of compounds of formula X, X*, A, and A*, L is bivalent, e.g., when n is 1 in formula X or A described herein. In other embodiments, L is multivalent, thereby linking multiple chelating moieties to the targeting moiety, e.g., when n is greater than 1, e.g., an integer between 2 and 10 in formula X or A described herein.

[0136] In certain embodiments of compounds of formulas X, X*, A, and A*, L comprises one or more chemical entities selected from an amino acid, a sequence of amino acids, a 5- to 7-membered carbocyclic or heterocyclic group, or a cyclic heterocyclic or acyclic organic molecule, any of which may optionally contain one or more functional groups selected from a ketone, an amide, an alkyne, an azide, an amine, and an isothiocyanate.

[0137] In certain embodiments of compounds of formula X, X*, A and A*, L is a linkage such that the targeting moiety is directly attached to the chelating moiety or moieties.

[0138] In certain embodiments of compounds of formula X, X*, A, and A*, L is a bivalent linker. In certain embodiments, L is a cleavable bivalent linker. Cleavable linkers include linkers that are cleaved by intracellular metabolism after internalization (e.g., cleavage by hydrolysis, reduction, or enzymatic reaction). In certain embodiments, L is a non-cleavable bivalent linker. Non-cleavable linkers include linkers that release the attached payload via lysosomal degradation after internalization.

[0139] In certain embodiments of compounds of formula X, X*, A, and A*, L is selected from an acid labile linker, a hydrolytically labile linker, an enzymatically cleavable linker, a reduction labile linker, a self-immolative linker, and a non-cleavable linker.

[0140] In certain embodiments of compounds of formula X, X*, A, and A*, L comprises one or more peptides, amino acids, glucuronides, succinimide thioethers, methylene units, carbonyl units, polyethylene glycol (PEG) units, hydrazones, mal-caproyl units, dipeptide units, valine-citrulline units, para-aminobenzyl (PAB) units, or combinations thereof.

[0141] In certain embodiments of compounds of formulas X, X*, A, and A*, L comprises one or more amino acids. Suitable amino acids include natural, unnatural, standard, non-standard, proteinogenic, non-proteinogenic, and L- or D-α-amino acids. In certain embodiments, the L linker 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 to 7 amino acids, 5 to 10 amino acids, 5 to 15 amino acids, or 10 to 15 amino acids. In certain embodiments, L is or comprises suberic acid-D-lysine-D-phenylalanine-3-iodo-D-tyrosine (Sub-kf-(Iy)) = 32 amino-29-benzyl-33-(4-hydroxy-3-iodophenyl)-5,13,20,28,31-pentaoxo-4,6,12,21,27,30-hexaazatritriacontane-1,3,7,26-tetracarboxylic acid.

[0142] In certain embodiments of compounds of formula X, X*, A, and A*, L is a divalent linker group or linking moiety. [ka] [ka] and [ka] is or contains

[0143] In certain embodiments of compounds of formula X, X*, A and A*, L is [ka] and [ka] In certain embodiments, L is or comprises [ka] In certain embodiments, L is or comprises [ka] [ka] and [ka] is or contains

[0144] In certain embodiments of compounds of formula X, X*, A and A*, L is selected from the group consisting of carbonyl, amine, amide, ester, ether, ethylenediamine [ka] or [ka] In certain embodiments, L is or comprises one or more of: [ka] In certain embodiments, L is or comprises [ka] is or contains

[0145] Suitable linkers are disclosed in U.S. Patent Application Publication No. US2011 / 0064657, published March 17, 2011, to Pomper et al., entitled "Labeled Inhibitors of Prostate Specific Membrane Antigen (PSMA), Biological Evaluation, and Use as Imaging Agents," and U.S. Patent Application Publication No. US2012 / 0009121, published January 12, 2012, to Pomper et al., entitled "PSMA-Targeting Compounds and Uses Thereof," each of which is incorporated by reference in its entirety.

[0146] 4.2.4. Targeting part The targeting moieties (V) for use with the present disclosure are not particularly limited, so long as one or more of the targeting moieties are suitable for conjugation with a chelating moiety as described herein and the targeting moiety interacts with a cell surface target.

[0147] In certain embodiments of compounds of Formulas X, X*, A, and A*, the targeting moiety is selected from a peptide, protein, or small organic molecule that binds to a cell surface receptor, e.g., expressed by malignant or pre-malignant cells; cells in the tumor microenvironment, such as blood vessels, cancer-associated fibroblasts, interstitial matrix and immune cells, inflamed tissue; and / or sites of tissue remodeling at sites of fibrosis in myocardial infarction or interstitial lung disease.

[0148] In certain embodiments of compounds of Formulas X, X*, A and A*, the targeting moieties are those known to target PSMA (prostate-specific membrane antigen), SSTR (somatostatin receptor) and FAP (fibroblast activation protein).

[0149] In certain embodiments of compounds of formula X, X*, A and A*, the targeting moiety is 68 Ga, 225 Ac or 177 These targeting moieties are known to be suitable for use with the 1 ...

[0150] In certain embodiments of compounds of Formulas X, X*, A, and A*, the targeting moiety is a peptide. The peptide may comprise 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 may comprise as many as 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, or 40-50 amino acids.

[0151] In certain embodiments of compounds of Formulas X, X*, A, and A*, the targeting moiety is specifically recognized by a molecular target (e.g., a peptide or protein) expressed, e.g., commonly overexpressed, on the surface of cancer cells or in the cancer microenvironment.

[0152] In certain embodiments of compounds of Formulas X, X*, A, and A*, the targeting moiety comprises a molecule homologous to a tumor-specific antigen (TSA) found only on associated cancer cells and not on healthy cells. In certain embodiments, the targeting moiety comprises a molecule homologous to a tumor-associated antigen (TAA) that is expressed at high levels on tumor cells but at lower levels on healthy cells.

[0153] In certain embodiments of the compounds of formulas X, X*, A, and A* of the targeted chelator constructs and radiotracers of the present disclosure, the targeting moiety comprises neurotensin or a functional derivative thereof. In certain embodiments, the targeting moiety comprises a molecule that binds to epidermal growth factor receptor 2 (HER2). In certain embodiments, the targeting moiety comprises a molecule that binds to prostate-specific antigen (PSA), also known as gamma-seminoprotein or kallikrein-3 (KLK3). In certain embodiments, the targeting moiety comprises a molecule that binds to tyrosinase-related protein-2 (TRP2), also known as dopachrome tautomerase. In certain embodiments, the targeting moiety comprises a molecule that binds to epithelial cell adhesion molecule (EpCAM). In certain embodiments, the targeting moiety comprises a molecule that binds to glypican-3 (GPC3). In certain embodiments, the targeting moiety comprises a molecule that binds to mesothelin (MSLN), integrin αvβ3, or prostate-specific membrane antigen (PSMA). In certain embodiments, the targeting moiety comprises a molecule that binds to somatostatin receptor (SSTR). In certain embodiments, the targeting moiety comprises a molecule that binds to fibroblast activation protein (FAP). In certain embodiments, the targeting moiety comprises a molecule that binds to epidermal growth factor receptor (EGFR).

[0154] 4.2.4.1.1 Target: Neurotensin Receptor In certain embodiments of compounds of formulas X, X*, A, and A*, the targeting moiety comprises neurotensin (NT) or a functional derivative thereof. In certain embodiments, targeting moieties comprising neurotensin have previously been demonstrated to have the potential to target tumors such as pancreatic, colorectal, lung, prostate, or breast cancer. In certain embodiments, the targeting moiety comprises (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu). In certain embodiments, the targeting moiety comprises 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]amino]adamantane-2-carboxylic acid US9868707B2.

[0155] 4.2.4.1.2 Target: Integrin αvβ3 Integrins, consisting of two noncovalently linked transmembrane α and β subunits, are a family of molecules important in tumor angiogenesis. Integrin αvβ3 is highly expressed on activated endothelial cells, neovascularization, and some tumor cells, but is absent on quiescent endothelial cells and most normal organ systems, making it a suitable target for antiangiogenic therapy.

[0156] In embodiments of the compounds of Formulas X, X*, A, and A*, the targeting moiety comprises a molecule that binds to integrin αβ or αβ. In certain embodiments, the targeting moiety comprises LM609 / Avastin, CNTO 95, c7E3 Fab, 17E6, Abegulin, or a functional derivative of any of these.

[0157] In certain embodiments of compounds of Formulas X, X*, A, and A*, the targeting moiety comprises a peptide that binds to αβ integrin. In certain embodiments, the targeting moiety is selected from RGD peptides, SC-68448, SCH221153, and S-247 (as shown below). In certain embodiments, the targeting moiety comprises a dimeric RGD peptide E-[c(RGDfK)]2 formed by two cyclic pentapeptides c(RGDfK) linked through glutamic acid residues. 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 a disintegrin, a family of low molecular weight (47-84 amino acids) RGD-containing cysteine-rich peptides derived from snake venom. [ka]

[0158] 4.2.4.1.3 Target: PSMA Prostate-specific membrane antigen (PSMA) is a 750-amino acid type II transmembrane glycoprotein that is highly expressed in prostate adenocarcinoma and shows limited expression in benign and extraprostatic tissues, and is therefore an ideal target for the diagnosis and management of prostate cancer.

[0159] In certain embodiments of compounds of formula X, X*, A, and A*, the targeting moiety comprises a peptide that binds to urea-based prostate-specific membrane antigen (PSMA). In certain embodiments, the targeting moiety comprises an L-lysine-urea-glutamate, such as Lys-urea-Glu, or a PSMA inhibitor based on a KuE motif.

[0160] In certain embodiments of compounds of formula X, X*, A and A*, V is a targeting moiety. In certain embodiments, V is [ka] [ka] and [ka] is a moiety selected from the group consisting of:

[0161] In certain embodiments of compounds of formula X, X*, A and A*, the targeting moiety is [ka] In certain embodiments of compounds of formula X, X*, A and A*, the targeting moiety comprises [ka] In certain embodiments of compounds of formula X, X*, A and A*, the targeting moiety comprises [ka] In certain embodiments of compounds of formula X, X*, A and A*, the targeting moiety comprises [ka] Includes:

[0164] In certain embodiments, the compound is a compound of formula X: [ka] or a pharmaceutically acceptable salt thereof; the chelating moiety is NODAGA; L is [ka] V is a targeting moiety that binds to PSMA; n is 1; m is 1; and p is 1.

[0162] In certain embodiments, the compound of formula X is a compound of formula 10: [ka] or a pharmaceutically acceptable salt thereof; V comprises a targeting moiety that binds to PSMA.

[0163] In certain embodiments, the compound is a compound of formula X*: [ka] or a pharmaceutically acceptable salt thereof; the chelating moiety is NODAGA; *Cu is 61 Cu, 62 Cu, 64 Cu and 67 a copper radionuclide selected from Cu; L is [ka] V is a targeting moiety that binds to PSMA; n is 1; m is 1; and p is 1.

[0164] In certain embodiments, a compound comprising a copper atom chelated by the compound of embodiment 1, wherein the compound has the structure of Formula 10*: [ka] or a pharmaceutically acceptable salt thereof; *Cu is 61 Cu, 62 Cu, 64 Cu and 67 Cu is a copper radionuclide selected from

[0165] 4.2.4.1.4 Target: SSTR Neuroendocrine tumors (NETs) are neoplasms that most frequently occur in the GI tract, pancreas, or lungs. Diagnosis of NETs is often delayed until the disease has progressed due to the variable and nonspecific nature of early symptoms. Therefore, curative surgical resection is not an option for most patients. Somatostatin analogs represent the cornerstone of treatment for patients with NETs.

[0166] In certain embodiments of compounds of Formulas 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 is a cyclic octapeptide analog of somatostatin, e.g., 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 -octreotate). 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 comprises D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr(ol), i.e., TOC, according to the following structure 1: [ka] represents the point of attachment to the chelating moiety or linker. a. [ka]

[0167] In certain embodiments of the compounds of formulas 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 Nucl Med 2011;52:1110-8) and is readily available from commercial sources or by routine synthesis. In certain embodiments, the targeting moiety is according to the following structure 2: [ka] represents the point of attachment to the chelating moiety or linker. [ka]

[0168] In certain embodiments, the compound is a compound of formula X: [ka] or a pharmaceutically acceptable salt thereof; the chelating moiety is NODAGA; L is a linker moiety; V is a targeting moiety SST that binds to SSTR; n is 1; m is 1; and p is 1.

[0169] In certain embodiments, the compound is a compound of formula X. In certain embodiments, the compound of formula X* is a compound of formula 20: [ka] or a pharmaceutically acceptable salt thereof; *Cu is 61 Cu, 62 Cu and 67 a copper radionuclide selected from Cu; L is a bond or linker moiety; SST is a targeting moiety that binds to the somatostatin receptor.

[0170] 4.2.4.1.5 Target FAP In certain embodiments of compounds of formulas 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 a FAP inhibitor structure, such as Val-boroPro, linagliptin, FAPI-02, or a functional derivative of any of these. Also included are FAP congeners 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: [ka]

[0171] Suitable FAP inhibitors are disclosed in International PCT Patent Application No. WO2019 / 154886 to Haberkorn et al., published August 15, 2019, which is incorporated herein by reference in its entirety.

[0172] The present disclosure provides a composition comprising a compound, wherein the compound is a compound of formula 30: [ka] R 1 is R a and; R 2 and R 3 are R aor together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring;

[0173] R a independently for each occurrence, 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 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 is cycloalkyl; n is an integer from 1 to 20; m is an integer from 1 to 20; *Cu is 61 Cu, 62 Cu, 64 Cu and 67 a copper radionuclide selected from Cu; or a pharmaceutically acceptable salt thereof.

[0174] In certain embodiments of compounds of Formula 30, R 1 is H. In certain embodiments of compounds of Formula 30, R 1 is 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 5-9heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 In certain embodiments of compounds of Formula 30, R 1 is H,C 1-10 Alkyl, 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′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0175] In certain embodiments of compounds of Formula 30, R 1 is H and C 1-10 In certain embodiments of compounds of Formula 30, R 1 is H. In certain embodiments of compounds of Formula 30, R 1 is C 1-10 In certain embodiments of compounds of Formula 30, R 1 is C1-C6 alkyl. In certain embodiments of compounds of Formula 30, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. In certain embodiments of compounds of Formula 30, R 1 is methyl.

[0176] In certain embodiments of compounds of Formula 30, R 2 is H. In certain embodiments of compounds of Formula 30, R 2 is C 1-10 Alkyl, 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′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0177] In certain embodiments of compounds of Formula 30, R 3 is H. In certain embodiments of compounds of Formula 30, R 3 is C 1-10 Alkyl, 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′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0178] In certain embodiments of compounds of Formula 30, R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9In certain embodiments of the compound of Formula 30, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle. In certain embodiments of the compound of formula 30, C 2-9 The heterocycle is a 5-membered heterocycle selected from pyrrolidine, pyrazolidine, and imidazoline. In certain embodiments of the compound of Formula 30, C 2-9 The heterocycle is a 6-membered heterocycle selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane. In certain embodiments of the compound of Formula 30, C 2-9 The heterocycle is piperazine.

[0179] In certain embodiments of compounds of Formula 30, n is an integer from 1 to 10. In certain embodiments of compounds of Formula 30, n is an integer from 1 to 5. In certain embodiments of compounds of Formula 30, n is 1, 2, 3, 4, or 5. In certain embodiments of compounds of Formula 30, n is 2.

[0180] In certain embodiments of compounds of Formula 30, m is an integer from 1 to 10. In certain embodiments of compounds of Formula 30, m is an integer from 1 to 5. In certain embodiments of compounds of Formula 30, m is 1, 2, 3, 4, or 5. In certain embodiments of compounds of Formula 30, m is 2.

[0181] In certain embodiments of the compound of Formula 30, *Cu is 61 Cu, 62 Cu, 64 Cu and 67 In certain embodiments of the compound of Formula 30, *Cu is a copper radionuclide selected from Cu. 61 In certain embodiments of the compound of Formula 30, *Cu is 62 In certain embodiments of the compound of Formula 30, *Cu is 64 In certain embodiments of the compound of Formula 30, *Cu is 62 In certain embodiments of the compound of Formula 30, *Cu is 67 It is Cu.

[0182] In certain embodiments of compounds of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H, n is an integer from 1 to 20, m is an integer from 1 to 20, and *Cu is 61 Cu and 67 In certain embodiments of the compound of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H, n is an integer from 1 to 10, m is an integer from 1 to 10, and *Cu is 61 Cu and 67 In certain embodiments of the compound of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H, n is an integer from 1 to 5, m is an integer from 1 to 5, and *Cu is 61 Cu and 67 In certain embodiments of the compound of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 is H and R 3 is H, n is 2, m is 2, and *Cu is 61 Cu and 67 Cu is a copper radionuclide selected from

[0183] In certain embodiments of compounds of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 forming a heterocyclic ring, n is an integer from 1 to 20, m is an integer from 1 to 20, and *Cu is 61 Cu and 67In certain embodiments of the compound of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 forming a heterocycle, n is an integer from 1 to 10, m is an integer from 1 to 10, and *Cu is 61 Cu and 67 In certain embodiments of the compound of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 forming a heterocycle, n is an integer from 1 to 5, m is an integer from 1 to 5, and *Cu is 61 Cu and 67 In certain embodiments of the compound of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 forming a heterocycle, n is 2, m is 2, and *Cu is 61 Cu and 67 Cu is a copper radionuclide selected from

[0184] In certain embodiments of compounds of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The 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 61 Cu and 67 In certain embodiments of the compound of Formula 30, R 1 is H and C 1-10alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The 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 61 Cu and 67 In certain embodiments of the compound of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The 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 61 Cu and 67 In certain embodiments of the compound of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a 5-, 6-, or 7-membered heterocycle, n is 2, m is 2, and *Cu is 61 Cu and 67 Cu is a copper radionuclide selected from

[0185] In certain embodiments of compounds of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The 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 61 Cu and 67 In certain embodiments of the compound of Formula 30, R 1 is H and C1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The 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 61 Cu and 67 In certain embodiments of the compound of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The 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 61 Cu and 67 In certain embodiments of the compound of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is a 6-membered heterocycle, n is 2, m is 2, and *Cu is 61 Cu and 67 Cu is a copper radionuclide selected from

[0186] In certain embodiments of compounds of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, m is an integer from 1 to 20, n is an integer from 1 to 20, and *Cu is 61 Cu and 67 In certain embodiments of the compound of Formula 30, R 1 is H and C1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, m is an integer from 1 to 10, n is an integer from 1 to 10, and *Cu is 61 Cu and 67 In certain embodiments of the compound of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, m is an integer from 1 to 5, n is an integer from 1 to 5, and *Cu is 61 Cu and 67 In certain embodiments of the compound of Formula 30, R 1 is H and C 1-10 alkyl, and R 2 and R 3 are both nitrogen atoms to which they are attached and C 2-9 Forming a heterocyclic ring, C 2-9 The heterocycle is piperazine, m is 2, n is 2, and *Cu is 61 Cu and 67 Cu is a copper radionuclide selected from

[0187] In certain embodiments of compounds of Formula 30, R 2 and R 3 taken together with the nitrogen atom to which they are attached form a piperazine and m is 2, thereby providing a compound of formula 30a: [ka]

[0188] or a pharmaceutically acceptable salt thereof, 1 , n and *Cu are as described above for Formula 30.

[0189] In certain embodiments of compounds of Formula 30a, R 1 is H. In certain embodiments of compounds of Formula 30a, R 1 is 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 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0190] In certain embodiments of compounds of Formula 30a, R 1 is H,C 1-10 Alkyl, 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′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0191] In certain embodiments of compounds of Formula 30a, R 1 is H and C1-10 In certain embodiments of compounds of Formula 30a, R 1 is H. In certain embodiments of compounds of Formula 30a, R 1 is C 1-10 In certain embodiments of compounds of Formula 30a, R 1 is C1-C6 alkyl. In certain embodiments of compounds of Formula 30a, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. In certain embodiments of compounds of Formula 30a, R 1 is methyl.

[0192] In certain embodiments of compounds of Formula 30a, n is an integer from 1 to 10. In certain embodiments of compounds of Formula 30a, n is an integer from 1 to 5. In certain embodiments of compounds of Formula 30a, n is 1, 2, 3, 4, or 5. In certain embodiments of compounds of Formula 30a, n is 2.

[0193] In certain embodiments of compounds of Formula 30a, *Cu is 61 Cu, 62 Cu, 64 Cu and 67 In certain embodiments of the compound of Formula 30a, *Cu is a copper radionuclide selected from Cu. 61 In certain embodiments of compounds of Formula 30a, *Cu is 62 In certain embodiments of compounds of Formula 30a, *Cu is 64 In certain embodiments of compounds of Formula 30a, *Cu is 62 In certain embodiments of compounds of Formula 30a, *Cu is 67 It is Cu.

[0194] In certain embodiments of compounds of Formula 30a, R 1 is H and C 1-10 alkyl, n is an integer from 1 to 20, and *Cu is 61 Cu and 67 In certain embodiments of the compound of Formula 30a, R 1is H and C 1-10 alkyl, n is an integer from 1 to 10, and *Cu is 61 Cu and 67 In certain embodiments of the compound of Formula 30a, R 1 is H and C 1-10 alkyl, n is an integer from 1 to 5, and *Cu is 61 Cu and 67 In certain embodiments of the compound of Formula 30a, R 1 is H and C 1-10 alkyl, n is 2, and Cu is 61 Cu and 67 Cu is a copper radionuclide selected from

[0195] In certain embodiments of compounds of Formula 30, R 2 and R 3 is H and m is 2, thereby providing a compound of formula 30b: [ka]

[0196] or a pharmaceutically acceptable salt thereof, 1 , n and *Cu are as described above for Formula 30.

[0197] In certain embodiments of compounds of Formula 30b, R 1 is H. In certain embodiments of compounds of Formula 30b, R 1 is 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 5-9heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0198] In certain embodiments of compounds of Formula 30b, R 1 is H,C 1-10 Alkyl, 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′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′, wherein R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 It is cycloalkyl.

[0199] In certain embodiments of compounds of Formula 30b, R 1 is H and C 1-10 In certain embodiments of compounds of Formula 30b, R 1 is H. In certain embodiments of compounds of Formula 30b, R 1 is C 1-10 In certain embodiments of compounds of Formula 30b, R 1is C1-C6 alkyl. In certain embodiments of compounds of Formula 30b, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. In certain embodiments of compounds of Formula 30b, R 1 is methyl.

[0200] In certain embodiments of compounds 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.

[0201] In certain embodiments of compounds of Formula 30b, *Cu is 61 Cu, 62 Cu, 64 Cu and 67 In certain embodiments of the compound of Formula 30b, *Cu is a copper radionuclide selected from Cu. 61 In certain embodiments of compounds of Formula 30b, *Cu is 62 In certain embodiments of compounds of Formula 30b, *Cu is 64 In certain embodiments of compounds of Formula 30b, *Cu is 62 In certain embodiments of compounds of Formula 30b, *Cu is 67 It is Cu.

[0202] In certain embodiments of compounds of Formula 30b, R 1 is H and C 1-10 alkyl, n is an integer from 1 to 20, and *Cu is 61 Cu and 67 In certain embodiments of compounds of Formula 30b, R 1 is H and C 1-10 alkyl, n is an integer from 1 to 10, and *Cu is 61 Cu and 67 In certain embodiments of compounds of Formula 30b, R 1 is H and C 1-10 alkyl, n is an integer from 1 to 5, and *Cu is61 Cu and 67 In certain embodiments of compounds of Formula 30b, R 1 is H and C 1-10 alkyl, n is 2, and Cu is 61 Cu and 67 Cu is a copper radionuclide selected from

[0203] In certain embodiments of compounds of formula 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 linker moiety are according to F1, F2, F3, F4 shown in the table below: [ka] represents the point of attachment to the chelating moiety. [Table 2]

[0204] 4.2.4.2 Exemplary Compounds In certain embodiments of compounds of formulas 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: 61 Cu, 62 Cu, 64 Cu and 67 Cu. In certain embodiments, Cu* is 61 Cu. In certain embodiments, Cu* is 67 It is Cu. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0205] In certain embodiments, the composition for use in medical imaging and / or therapy comprises a specific radionuclide for use in medical imaging or therapy, e.g. 64 Cu, 68 Ga or 177 Included are targeted chelator constructs known in the art to be useful for chelating Lu.

[0206] Such targeted chelator constructs include compounds of structures 8-14 shown below. [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0207] In certain embodiments of compounds of formulas X and A, the compound is selected from structures 1-19 above, or a pharmaceutically acceptable salt thereof, and the chelating moiety is replaced with any chelating moiety known to chelate Ga, Lu, or Cu, or a chelating moiety exemplified in the section entitled Chelating Moieties herein.

[0208] In certain embodiments of compounds of formula X and A, the compound is selected from one of structures 15-24 shown below, or a pharmaceutically acceptable salt thereof. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0209] In certain embodiments of compounds of formula X* and A*, the compound is selected from one of structures 25-34 shown below, or a pharmaceutically acceptable salt thereof.

[0210] In certain embodiments, the diagnostic radiotracer is selected from compounds 25-34. [Table 4-1] [Table 4-2] [Table 4-3]

[0211] In certain embodiments of compounds of formulas X* and A*, the compound is selected from one of structures 35-43 shown below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a therapeutic radiotracer. [Table 5-1] [Table 5-2] [Table 5-3]

[0212] Pharmaceutical Compositions One aspect of the present disclosure provides high-purity pharmaceutical compositions comprising compounds of formula X*, formula A*, or pharmaceutically acceptable salts thereof. In certain embodiments, these compositions are for use in medical imaging (imaging diagnosis) and / or therapy. In another aspect, the present invention provides pharmaceutical compositions comprising compounds of the present disclosure, including formula X* and A*, and examples, in combination with a pharmaceutically acceptable excipient (e.g., carrier).

[0213] The pharmaceutical compositions include optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors disclosed herein.

[0214] As used herein, "pharmaceutically acceptable carrier" refers to a pharmaceutical excipient, e.g., a pharmaceutically, physiologically acceptable organic or inorganic carrier substance suitable for enteral or parenteral administration that does not adversely react with the active agent. Suitable pharmaceutically acceptable carriers include water, salt solutions (such as Ringer's solution), alcohol, oil, gelatin, and carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidone. Such preparations may be sterilized and, if necessary, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, coloring agents, and / or aromatic substances that do not adversely react with the compounds of the present invention.

[0215] The compound of the present invention can be administered to a subject alone or simultaneously. Simultaneous administration means that the compound is administered individually or in combination (two or more compounds) simultaneously or sequentially.If necessary, the preparation can also be combined with other active substances (for example, to reduce metabolic degradation).

[0216] In certain embodiments, the compounds described herein can be incorporated into pharmaceutical compositions for administration by methods known to those of skill in the art and described herein for the provided compounds.

[0217] In certain embodiments, a pharmaceutical composition according to the present disclosure comprises a compound of formula X, X*, A, and A*, wherein the composition further comprises a pharmaceutically acceptable excipient.

[0218] In certain embodiments, pharmaceutical compositions according to the present disclosure are characterized by one or more of the activity and purity characteristics described below.

[0219] Radioactivity As used herein, the term "radioactivity" (also called activity or total activity) refers to a physical quantity defined as the number of radioactive transformations per second that occur in a particular radionuclide. The unit of radioactivity as used herein is the becquerel (symbol Bq), which is the reciprocal of 1 / s or s -1 ) is defined as equivalent to

[0220] 4.3.2 Molar Radioactivity As used herein, the term "molar radioactivity" refers to the amount of radioactivity (e.g., nuclear disintegrations per second) per mole of a radiolabeled compound, expressed in Bq / mol, e.g., GBq / μmol, and is used when the molecular weight of the labeled material is known.

[0221] In certain embodiments, the molar radioactivity of the composition is between 1 and 280 MBq / nmol, e.g., between 5 and 265 MBq / nmol, 10 and 250 MBq / nmol, 15 and 235 MBq / nmol, 20 and 220 MBq / nmol, 25 and 205 MBq / nmol, 30 and 190 MBq / nmol, 35 and 175 MBq / nmol, 40 and 160 MBq / nmol, 45 and 150 MBq / nmol, 50 and 135 MBq / nmol , 55-120 MBq / nmol, 1-50 MBq / nmol, 2-48 MBq / nmol, 4-46 MBq / nmol, 6-44 MBq / nmol, 8-42 MBq / nmol, 10-40 MBq / nmol, 12-38 MBq / nmol, 14-36 MBq / nmol, 16-34 MBq / nmol, 18-32 MBq / nmol, 20-30 MBq / nmol, or 22-28 MBq / nmol. In certain embodiments, the composition has a molar radioactivity of 24 MBq / nmol±3 MBq / nmol.

[0222] In certain embodiments, the molar radioactivity of the composition is 35 MBq / nmol or greater, 40 MBq / nmol or greater, 45 MBq / nmol or greater, 50 MBq / nmol or greater, 55 MBq / nmol or greater, 60 MBq / nmol or greater, 65 MBq / nmol or greater, 70 MBq / nmol or greater, 75 MBq / nmol or greater, 80 MBq / nmol or greater, 85 MBq / nmol or greater, 90 MBq / nmol or greater, 95 MBq / nmol or greater, 100 MBq / nmol or greater, 105 MBq / nmol or greater, 110 MBq / nmol or greater, 115 MBq / nmol or greater. , 120MBq / nmol or more, 125MBq / nmol or more, 130MBq / nmol or more, 135MBq / nmol or more, 140MBq / nmol or more, 145MBq / nmol or more, 150MBq / nmol or more, 155MBq / nmol or more, 160MBq / nmol or more, 165MBq / nmol or more, 170MBq / nmol or more, 175MBq / nmol or more, 180MBq / nmol or more, 185MBq / nmol or more, 190MBq / nmol or more, 195MBq / nmol or more, or 200MBq / nmol or more.

[0223] In certain embodiments, the molar radioactivity of the composition is 1-250 MBq / nmol, e.g., 1-200 MBq / nmol, 1-150 MBq / nmol, 1-100 MBq / nmol, 1-50 MBq / nmol, 50-250 MBq / nmol, 50-200 MBq / nmol, 50-150 MBq / nmol, 50-100 MBq / nmol, 100-250 MBq / nmol, 100-150 MBq / nmol, 150-250 MBq / nmol, 150-200 MBq / nmol, or 200-250 MBq / nmol. In certain embodiments, the radiotracer composition is characterized by a molar radioactivity of 1-150 MBq / nmol.

[0224] In certain embodiments, the molar radioactivity of the composition is 90 MBq / nmol or more, 88 MBq / nmol or more, 86 MBq / nmol or more, 84 MBq / nmol or more, 82 MBq / nmol or more, 80 MBq / nmol or more, 78 MBq / nmol or more, 76 MBq / nmol or more, 74 MBq / nmol or more, 72 MBq / nmol or more, 70 MBq / nmol or more, 68 MBq / nmol or more, 66 MBq / nmol or more, 64 MBq / nmol or more, 62 MBq / nmol or more, 60 MBq / nmol or more, 58 MBq / nmol or more, 56 MBq / nmol or more, 54 MBq / nmol or more, 52 MBq / nmol or more, 50 MBq / nmol or more, 48 MBq / nmol or more, 46 MBq / nmol or more, 44 MBq / nmol or more, or 42 MBq / nmol or more.

[0225] In certain embodiments of the composition, the molar radioactivity of the composition is 3 MBq / nmol or more, 4 MBq / nmol or more, 5 MBq / nmol or more, 6 MBq / nmol or more, 7 MBq / nmol or more, 8 MBq / nmol or more, 9 MBq / nmol or more, 10 MBq / nmol or more, 11 MBq / nmol or more, 12 MBq / nmol or more, 13 MBq / nmol or more, 14 MBq / nmol or more, 15 MBq / nmol or more, 16 MBq / nmol or more, 17 MBq / nmol or more, 18 MBq / nmol or more, or 19 MBq / nmol or more.

[0226] In certain embodiments of the composition, the molar radioactivity of the composition is 3 MBq / nmol or more, 5 MBq / nmol or more, 10 MBq / nmol or more, 15 MBq / nmol or more, 20 MBq / nmol or more, 25 MBq / nmol or more, 30 MBq / nmol or more, 35 MBq / nmol or more, 40 MBq / nmol or more, 45 MBq / nmol or more, 50 MBq / nmol or more, 55 MBq / nmol or more, 60 MBq / nmol or more, 65 MBq / nmol or more. mol or more, 70MBq / nmol or more, 75MBq / nmol or more, 80MBq / nmol or more, 85MBq / nmol or more, 90MBq / nmol or more, 95MBq / nmol or more, 100MBq / nmol or more, 1 05MBq / nmol or more, 110MBq / nmol or more, 115MBq / nmol or more, 120MBq / nmol or more, 125MBq / nmol or more, 130MBq / nmol, 135MBq / nmol, 140MBq / nmol, 145MBq / nmol or more, 150MBq / nmol, 155MBq / nmol, 160MBq / nmol or more, 165MBq / nmol or more, 170MBq / nmol or more, 175MBq / nmol or more, 180MBq / nmol or more, 185MBq / nmol or more, 190MBq / nmol or more, 195MBq / nmol or more, 200MBq / nmol or more, 205MBq / nmol or more, 210MBq / nmol or more, 21 In certain embodiments, the composition has a molar radioactivity of 5 MBq / nmol or greater, 220 MBq / nmol or greater, 225 MBq / nmol or greater, 230 MBq / nmol or greater, 235 MBq / nmol or greater, 240 MBq / nmol or greater, 245 MBq / nmol or greater, 250 MBq / nmol or greater, 255 MBq / nmol or greater, 260 MBq / nmol or greater, 265 MBq / nmol or greater, 270 MBq / nmol or greater, 275 MBq / nmol or greater, or 280 MBq / nmol or greater.

[0227] In certain embodiments, the molar radioactivity of the composition is 1 to 250 MBq / nmol, e.g., 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.

[0228] 4.3.3. Radioactivity concentration As used herein, the term "radioactivity concentration" refers to the total amount of radioactivity per unit volume. In certain embodiments, the radioactivity concentration is expressed in Bq / L or its magnitude (e.g., MBq / mL).

[0229] In certain embodiments, the compositions provided herein are characterized by a radioactivity concentration of 8 MBq / mL or greater. In certain embodiments, the compositions provided herein are characterized by a radioactivity concentration of 8-10 MBq / mL, 10-20 MBq / mL, 20-30 MBq / mL, 30-40 MBq / mL, 40-50 MBq / mL, 50-60 MBq / mL, 60-70 MBq / mL, 70-80 MBq / mL, 80-90 MBq / mL, 90-100 MBq / mL, 100-110 MBq / mL, 110-120 MBq / mL, 120-130 MBq / mL, 130-140 MBq / mL, 140-150 MBq / mL, 150-160 MBq / mL, 160-170 MBq / mL, or any combination thereof. 250 ~260MBq / mL, 260~270MBq / mL, 270~280MBq / mL, 280~290MBq / mL, 290~300MBq / mL, 300~310MBq / mL, 310~320MBq / mL, 320~330MBq / mL, 330~340MBq / mL, 340~350MBq / mL, 350~360MBq / mL, 360~370MBq / mL, 370~380MBq / mL, 380~390MBq / mL, 390~400MBq / mL, 400~410MBq / mL, 410~420MBq / mL, 420~ 430MBq / mL, 430~440MBq / mL, 440~450MBq / mL, 450~460MBq / mL, 460~470MBq / mL, 470~480MBq / mL, 480~490MBq / mL, 490~500MBq / mL, 500~510MBq / m L, 510~520MBq / mL, 520~530MBq / mL, 530~540MBq / mL, 540~550MBq / mL, 550~560MBq / mL, 560~570MBq / mL, 570~580MBq / mL, 580~590MBq / mL, 590~60 0MBq / mL, 600~610MBq / mL, 610~620MBq / mL, 620~630MBq / mL, 630~640MBq / mL, 640~650MBq / mL, 650~660MBq / mL, 660~670MBq / mL, 670~680MBq / mL,680~690MBq / mL, 690~700MBq / mL, 700~710MBq / mL, 710~720MBq / mL, 720~730MBq / mL, 730~740MBq / mL, 740~750MBq / mL, 750~760MBq / mL, 760 ~770MBq / mL, 770~780MBq / mL, 780~790MBq / mL, 790~800MBq / mL, 800~810MBq / mL, 810~820MBq / mL, 820~830MBq / mL, 830~840MBq / mL, 840~850 The radioactivity concentration is 850-860MBq / mL, 860-870MBq / mL, 870-880MBq / mL, 880-890MBq / mL, 890-900MBq / mL, 900-910MBq / mL, 910-920MBq / mL, 920-930MBq / mL, 930-940MBq / mL, 940-950MBq / mL, 950-960MBq / mL, 960-970MBq / mL, 970-980MBq / mL, 980-990MBq / mL or 990-1000MBq / mL.

[0230] In certain embodiments, provided compositions are characterized by a radioactivity concentration of 8 MBq / mL or greater, 5-500 MBq / mL, 20-480 MBq / mL, 40-460 MBq / mL, 60-440 MBq / mL, 80-420 MBq / mL, 100-400 MBq / mL, 120-380 MBq / mL, 140-360 MBq / mL, 160-340 MBq / mL, 180-320 MBq / mL, or 200-300 MBq / mL.

[0231] In certain embodiments, provided compositions comprise a serotonin concentration of 3 MBq / mL or more, 4 MBq / mL or more, 5 MBq / mL or more, 6 MBq / mL or more, 7 MBq / mL or more, 8 MBq / mL or more, 9 MBq / mL or more, 10 MBq / mL or more, 12 MBq / mL or more, 15 MBq / mL or more, 20 MBq / mL or more, 25 MBq / mL or more, 30 MBq / mL or more, 35 MBq / mL or more, 40 MBq / mL or more, 45 MBq / mL or more, 50MBq / mL or more, 55MBq / mL or more, 60MBq / mL or more, 65MBq / mL or more, 70MBq / mL or more, 75MBq / mL or more, 80MBq / mL or more, 85MBq / mL or more, 90MBq / mL or more, 95MBq / mL or more, 100MBq / mL or more, 105MBq / mL or more, 110MBq / mL or more, 115MBq / mL or more, 120MBq / mL or more, 125MBq / mL or more, 130MBq / mL or more, 135MBq / mL or more, 140MBq / mL or more, 145MBq / mL or more, 150MBq / mL or more, 155MBq / mL or more, 160MBq / mL or more, 165MBq / mL or more, 170MB q / mL or more, 175MBq / mL or more, 180MBq / mL or more, 185MBq / mL or more, 190MBq / mL or more, 195MBq / mL or more, 200MBq / mL or more, 205MBq / mL or more, 210M It is characterized by a radioactivity concentration of ≥ 215MBq / mL, ≥ 220MBq / mL, ≥ 225MBq / mL, ≥ 230MBq / mL, ≥ 235MBq / mL, ≥ 240MBq / mL, ≥ 245MBq / mL, ≥ 250MBq / mL, ≥ 255MBq / mL, ≥ 260MBq / mL, ≥ 265MBq / mL, ≥ 270MBq / mL, ≥ 275MBq / mL, or ≥ 280MBq / mL.

[0232] In certain embodiments, the radioactivity concentration of the resulting pharmaceutical composition may be diluted (e.g., 3- to 10-fold) as long as the radioactivity concentration remains at or above 8 MBq / mL. In certain embodiments, the radioactivity concentration of the composition is 8-20 MBq / mL, 9-19 MBq / mL, 10-18 MBq / mL, 11-19 MBq / mL, 12-18 MBq / mL, 13-15 MBq / mL, 14-15 MBq / mL, 8-14 MBq / mL, 8-13 MBq / mL, 8-12 MBq / mL, 8-11 MBq / mL, 8-10 MBq / mL, 8-9 MBq / mL, 9-14 MBq / mL, 10-13 MBq / mL, or 11-12 MBq / mL.

[0233] In certain embodiments, provided pharmaceutical compositions are characterized by a radioactivity concentration of 0.3 to 0.75 GBq / mL.

[0234] 4.3.4. Radiochemical purity "Radiochemical purity," as understood herein, is the ratio, given as a percentage, of the radioactivity from the desired radionuclide in a radiopharmaceutical composition (e.g., the desired radionuclide chelated with a radiotracer described herein) to the total radioactivity of the composition containing the radiopharmaceutical. It is important to know that the majority of the radioisotope is bound to the tracer construct and not free or bound to another chemical entity, because these forms may have different biodistributions. Radiochemical purity (RCP) measurements establish the content of impurities labeled with the same radionuclide but in a different chemical form than that used to prepare the radiopharmaceutical. For most radiopharmaceuticals, the lower limit of radiochemical purity is 95%, i.e., at least 95% of the radioisotope must be bound to the ligand. Radiochemical purity determination can be performed by various chromatographic methods.

[0235] Radiochemical purity is determined according to methods well known to those skilled in the art, such as radio-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 of the peak area of ​​the desired radiopharmaceutical to the total area (decay-corrected) of all peaks detected in the radiochromatogram. The instrument used to determine radiochemical purity using HPLC (radio-HPLC) is a radiometric detector (radiodetector) with an in-line detector connected in series with a UV or other physicochemical detector. The radiation detector can be a Geiger-Muller probe, a scintillation detector, or a PIN diode. Compared to radio-HPLC, it has the significant advantage that all applied radioactivity is detected and there are no concerns about recovery.

[0236] In certain embodiments, the composition is characterized by a radiochemical purity of 90% or greater. In certain embodiments, the composition is characterized by a radiochemical purity of 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater. In certain embodiments, the composition is characterized by a radiochemical purity of 90% or greater. In certain embodiments, the composition is characterized by a radiochemical purity of 95% or greater. In certain embodiments, the composition is characterized by a radiochemical purity of 96% or greater. In certain embodiments, the composition is characterized by a radiochemical purity of 98% or greater.

[0237] In certain embodiments, provided compositions are characterized by a radiochemical purity of 94.0% or greater, 94.5% or greater, 95.0% or greater, 95.5% or greater, 96.0% or greater, 96.5% or greater, 97.0% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater.

[0238] In certain embodiments, provided compositions are characterized by a radiochemical purity of 95.2% or greater, 95.4% or greater, 95.6% or greater, 95.8% or greater, 96% or greater, 96.2% or greater, 96.4% or greater, 96.6% or greater, 96.8% or greater, 97% or greater, 97.2% or greater, 97.4% or greater, 97.6% or greater, 97.8% or greater, 98% or greater, 98.2% or greater, 98.4% or greater, 98.6% or greater, 98.8% or greater, 99% or greater, 99.2% or greater, 99.4% or greater, 99.6% or greater, or 99.8% or greater.

[0239] 4.3.5. Radionuclide Purity As used herein, the term "radionuclide purity" refers to the ratio, expressed as a percentage, of the radioactivity of a desired radionuclide to the total radioactivity of starting materials used to prepare a sample, e.g., a radiolabeled pharmaceutical. As reported herein, unless otherwise specified, radionuclide purity is determined by high-resolution gamma spectroscopy (e.g., high-purity germanium (HPGe) detector) of the sample post-exhalation, e.g., >8 hours or >3 weeks), and then extrapolated (e.g., using the TENDLE-2019 database according to procedures well known in the art) and reported herein as the value at the end of synthesis of the radionuclide (EoB + 2 hours).

[0240] In certain embodiments, the composition is characterized in that the radionuclide purity of the compound at the end of synthesis is 85% or greater, e.g., 86% or greater, 87% or greater, 88% or greater, 89% or greater, 90% or greater, 91% or greater, 92% or greater, 93% or greater, 94% or greater, 95% or greater, 96% or greater, 97% or greater, 98% or greater, or 99% or greater.

[0241] In certain embodiments, the composition is characterized in that the radionuclide purity of the compound at the end of synthesis is 90.5% or greater, e.g., 91% or greater, 91.5% or greater, 92% or greater, 92.5% or greater, 93% or greater, 93.5% or greater, 94% or greater, 94.5% or greater, 95% or greater, 95.5% or greater, 96% or greater, 96.5% or greater, 97% or greater, 97.5% or greater, 98% or greater, 98.5% or greater, 99% or greater, or 99.5% or greater.

[0242] In certain embodiments, the composition has a cytoplasmic ... Characterized by a radionuclide purity of ≥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%.

[0243] In certain embodiments, the composition is characterized by a radionuclide purity of 97% or greater (at the end of synthesis). In certain embodiments, the composition is characterized by a radionuclide purity of 93% or greater, 94% or greater, 95% or greater, 96% or greater, 98% or greater, or 99% or greater (at the end of synthesis).

[0244] 4.3.6 Formulation The compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (e.g., intravenous, intramuscular, intradermal, subcutaneous, intraduodenal, or intraperitoneal). In certain embodiments, the compounds of the present disclosure are administered orally. The compounds described herein can also be administered by inhalation, for example, intranasally. Furthermore, the compounds of the present invention can be administered transdermally. It is also contemplated that multiple administration routes (e.g., intramuscular, oral, transdermal) can be used to administer the compounds of the present invention. Thus, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the present invention.

[0245] For preparing pharmaceutical compositions from the compound of the present invention, pharmaceutically acceptable carrier can be either solid or liquid.Solid preparations include powder, tablet, pill, capsule, cachet, suppository and dispersible granule.Solid carrier can be one or more substances that can also act as diluent, flavoring agent, binder, preservative, tablet disintegrating agent or encapsulating material.

[0246] In powders, the carrier is a finely divided solid in admixture with the finely divided active component. In tablets, the active component is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0247] Effective Dose The pharmaceutical compositions provided by the present disclosure include compositions containing an active ingredient in a therapeutically effective amount, i.e., an amount effective to achieve its intended purpose. The actual amount effective for a particular application will depend, among other things, on the condition being treated or the image being generated. For example, when administered in a method for treating cancer, such a composition will contain an amount of active ingredient effective to achieve the desired result (e.g., imaging of cancerous tissue and / or reducing the amount of cancerous tissue in a subject).

[0248] The dosage and frequency (single dose or multiple doses) of the compound to be administered can vary depending on various factors, including the route of administration; the size, age, sex, health condition, 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 complications from any disease or treatment regimen. Other treatment regimens or drugs can be used in conjunction with the methods and compounds of the present invention.

[0249] For any compound or test agent provided, the diagnostically or therapeutically effective amount can be initially determined from cell culture assays and / or animal studies. The target concentration is the concentration of the active compound that is capable of diagnosing, monitoring, and / or treating cancer in a patient or subject.

[0250] The therapeutically effective amount for human use can be determined from animal models.For example, the dose for human can be formulated to achieve the concentration that has been found to be effective in animals.The dose for human can be adjusted by monitoring cancerous growth, proliferation and / or metastasis, and adjusting the dose upward or downward, as described above.

[0251] Dosage can be varied depending on the requirements of the patient and the compound used.In the context of the present invention, the dose administered to the patient should be sufficient to affect the patient's beneficial therapeutic response over time.The size of the dose is also determined by dose escalation test during clinical trial stage.

[0252] In one aspect, the compounds provided herein exhibit one or more improved pharmacokinetic (PK) properties (e.g., Cmax, tmax, Cmin, t1 / 2, AUC, CL, bioavailability, etc.) when compared to a reference compound. In certain embodiments, the reference compound is an aPSMA, SSTR2, or FAP PET radiotracer.

[0253] In certain embodiments, the compounds of the present disclosure or pharmaceutical compositions comprising same are provided as unit doses. In certain embodiments, the compounds of the present disclosure or radiopharmaceutical compositions comprising same are provided as unit doses (e.g., molar radioactivity).

[0254] In certain embodiments, the pharmaceutical compositions of the present disclosure are administered in combination 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 receiving any one of spironolactone, bumetanide, ethacrynic acid, torasemide, hydrochlorothiazide, furosemide, or metolazone.

[0255] In certain embodiments, the pharmaceutical compositions of the present disclosure are administered to a subject who is also receiving any one of the drugs selected from lysine, gelofuscin, docetaxel, everolimus, abiraterone acetate, enzalutamide, olaparib, temozolomide, acetazolamide, or succinylacetone.

[0256] 4.4.How to use The present disclosure provides compounds and pharmaceutical compositions comprising same for use in medicine, i.e., for use in therapy, imaging, diagnosis, companion diagnostics, etc. The present disclosure further provides the use of any of the compounds described herein for targeted radiation therapy, which would be beneficial in the diagnosis and / or treatment of cancer.

[0257] In certain embodiments, the compound or pharmaceutical composition of the present disclosure is administered to a subject once a day, twice a day, every day, or every other day. In certain embodiments, the compound or pharmaceutical composition of the present disclosure is administered to a subject twice a week, once a week, every 10 days, every 2 weeks, every 3 weeks, every 4 weeks, every month, every 6 weeks, every 8 weeks, every 3 months, every 4 months, every 6 months, every 8 months, every 9 months, or every year. The dose and frequency (single dose or multiple doses) of the compound or pharmaceutical composition administered can vary depending on various factors, including the route of administration; the recipient's size, age, sex, health, weight, body mass index, and diet; the nature and severity of the symptoms of the disease being treated (e.g., disease-responsive treatment) and complications from any disease or treatment regimen. Other treatment regimens or drugs can be used in conjunction with the methods and compounds of the present invention.

[0258] For any compound or pharmaceutical composition provided, the effective amount (e.g., a diagnostically or therapeutically effective amount) can be initially determined from cell culture assays and / or animal studies. The target concentration is the concentration of the radioactive compound that is capable of diagnosing, monitoring, and / or treating cancer in a patient or subject.

[0259] The therapeutic efficacy of a compound may be determined from animal models. Human dosages can be adjusted during clinical trials via dose escalation studies by monitoring safety and efficacy.

[0260] Dosage can vary depending on the requirements 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 affect beneficial therapeutic responses in the patient over time.The size of the dosage will also be determined by the existence, nature and extent of adverse side effects.

[0261] In one aspect, the compounds provided herein exhibit one or more improved pharmacokinetic (PK) properties (e.g., Cmax, tmax, Cmin, t1 / 2, AUC, CL, bioavailability, etc.) when compared to a reference compound.

[0262] In some embodiments, a compound of the present disclosure or a pharmaceutical composition comprising same is provided as a unit dose.

[0263] In a further aspect, the present disclosure provides a novel radiotracer and / or novel radiotracer composition as provided hereinabove for use in a method for 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 carcinoma, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

[0264] In certain embodiments, the cancer is prostate cancer.Prostate cancer is not the only cancer that expresses PSMA.Non-prostate cancers known to express PSMA include breast cancer, lung cancer, colorectal cancer and renal cell carcinoma.Therefore, any compound described herein that has a PSMA binding moiety can be used for the diagnosis, imaging or treatment of cancers that express PSMA.Preferred indications include, but are not limited to, the detection or staging of cancers such as high-grade glioma, lung cancer, particularly prostate cancer and metastatic prostate cancer, the detection of metastatic disease in high-risk to medium-risk primary prostate cancer patients, and the detection of metastatic sites (even in patients with biochemical recurrence of prostate cancer with low serum PSA levels).Another preferred indication is the imaging and visualization of neovascularization.

[0265] With respect to medical indications amenable to treatment, particularly radiation therapy, cancer is a preferred indication, with prostate cancer being a particularly preferred indication.

[0266] In certain embodiments, the method comprises administering any of the compounds described herein or a pharmaceutically acceptable salt thereof to a subject (e.g., a subject such as a human patient) in need thereof. In certain embodiments, the method comprises administering a compound of formula X*, A*, 10*, a compound of structures 24-36 provided herein, or a pharmaceutically acceptable salt or composition of any of these, to a subject in need thereof. In certain embodiments, the method comprises administering a pharmaceutical composition comprising a compound of formula X* or A*, a compound of structures 24-36 provided, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0267] 4.4.1.1 Imaging and diagnostics In one aspect of the disclosure, there is provided a method of generating an image of a subject, e.g., a specific region or part of the body, comprising administering to the subject a compound described herein that comprises a radionuclide. In certain embodiments, the radionuclide is 60 Cu, 61 Cu, 62 Cu, 64 Cu and 67 In certain embodiments, the radionuclide is selected from Cu. 61 In certain embodiments, the radionuclide is Cu. 67 It is Cu.

[0268] In certain embodiments, a method for generating one or more images of a subject (e.g., of a particular region or portion of the subject's body) is provided, the method comprising administering to the subject an effective amount of a compound comprising a radionuclide as described herein or a pharmaceutical composition comprising the same, 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 same, i.e., an amount sufficient to identify (visually or computationally) the localization of the radionuclide within a region or portion of the subject's body, is administered to the subject. In some embodiments, the radionuclide is a metallic radionuclide. In certain embodiments, the radionuclide is60 Cu, 61 Cu, 62 Cu, 64 Cu and 67 In some embodiments, the radionuclide is selected from Cu. 61 It is Cu.

[0269] In certain embodiments, the one or more images are generated using positron emission tomography (PET). In certain embodiments, the one or more images are generated using PET-computed tomography (PET-CT). In certain embodiments, the one or more images are generated using single-photon emission computed tomography (SPECT).

[0270] In certain embodiments, the images are generated using PET or PET-CT, and the radionuclide is 61 In certain embodiments, the image is 61 Cu or 67 Generated using SPECT, which is Cu.

[0271] In certain embodiments, after one or more images are generated, the method further includes determining the presence or absence of disease in the subject based on the presence or absence of localization of the radionuclide in the one or more images of the subject's body.

[0272] In another aspect of the present disclosure, a method for monitoring the effect of cancer treatment on a subject suffering from cancer is provided, the method comprising administering to the subject a compound described herein that includes a radionuclide, detecting the localization of the compound in the subject using, for example, PET or SPECT, and determining the effect of the cancer treatment. In certain embodiments, the compound is administered to the subject, and localization is observed at multiple time points, i.e., an earlier time point (e.g., before the start of cancer treatment (t=0)) and a later time point, for example, 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 or more after the start of treatment. If less localization is observed at the later time point compared to the earlier time point, the cancer treatment is determined to be beneficial (i.e., a positive effect). If more localization is observed at the later time point compared to the earlier time point, the cancer treatment is determined to be not beneficial (i.e., an adverse effect). If there is no difference in localization at the later time point compared to the earlier time point, the cancer treatment is determined to be ineffective.

[0273] In certain embodiments, the diseases detected include cancers, such as neuroendocrine tumors, somatostatin receptor-expressing tumors such as prostate cancer and malignant meningiomas, epithelial cancers 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. 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, clear cell renal carcinoma, neuroendocrine tumors, oncogenetic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

[0274] Another aspect of the present disclosure provides a method for monitoring the effectiveness of cancer treatment in a subject suffering from cancer. The method includes administering to the subject an effective amount of a compound containing a radionuclide or a pharmaceutical composition containing the same as described herein, detecting the localization of the radionuclide in the subject using, for example, PET, PET-CT, or SPECT, and determining the effectiveness of the cancer treatment. In certain embodiments, a compound containing a radionuclide or a pharmaceutical composition containing the same is administered to the subject, and localization is observed at multiple time points, i.e., an earlier time point (e.g., before cancer treatment is initiated (t=0)) and a later time point, for example, 2 weeks after initiation of treatment, 3 weeks after initiation of treatment, 1 month after initiation of treatment, 2 months after initiation of treatment, 3 months after initiation of treatment, 4 months after initiation of treatment, 5 months after initiation of treatment, or 6 months or more after initiation of treatment. In certain, but not all, embodiments, the cancer treatment is determined to be beneficial (i.e., a positive effect) if less localization is observed at the later time point compared to the earlier time point. In certain, but not all, embodiments, a cancer treatment is determined to be not beneficial (i.e., adverse) if more localization is observed at later time points compared to earlier time points. In certain, but not all, embodiments, a cancer treatment is determined to be ineffective if there is no difference in localization at later time points compared to earlier time points.

[0275] 4.4.1.2 Treatment In one aspect of the disclosure, there is provided a method of treating a disease in a patient suffering from the disease, the treatment comprising administering to the patient an effective amount of a compound or pharmaceutical composition described herein.

[0276] In certain embodiments, a method of providing radionuclide therapy to a cancer patient in need thereof is provided, the method comprising administering to the cancer patient an effective amount of a high purity radiotracer composition described herein, wherein *Cu is 64 Cu or 67 It is Cu.

[0277] In certain embodiments, the compound administered is a compound of formula X, 64 Cu and 67Such embodiments include radionuclides selected from Cu. Such embodiments are useful in treating cancer, 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 carcinoma, esophageal cancer, hypopharyngeal cancer, nasopharyngeal carcinoma, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumors, oncogene osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

[0278] In further embodiments of the above methods, the cancer is selected from FAP-overexpressing epithelial cancers, including neuroendocrine tumors, prostate cancer, somatostatin receptor-expressing tumors such as malignant meningiomas, non-small cell lung cancer, triple-negative breast cancer, head and neck cancer, colorectal cancer, gastric cancer, ovarian cancer, and pancreatic cancer.

[0279] 4.4.1.3 Theranostics In one aspect of the present disclosure, theranostic methods, as provided herein, involve the use of pairs of Cu radiotracers ("theranostic pairs") for both imaging / diagnosis of disease and for treatment of disease in the same patient, where the theranostic pair of radiotracers differs only in the radionuclide, i.e., different radioisotopes. In certain embodiments, the theranostic pair includes a gamma- or positron-emitting radionuclide in the radiotracer for imaging / diagnosis (e.g., using PET, PET-CT, or SPECT) and a beta-emitting radionuclide in the radiotracer for treatment.

[0280] In certain embodiments, theranostic couples include: 61 Cu (imaging / diagnostic) and 67 Cu (therapeutic). In certain embodiments, 61 / 67 Called Cu Theranostic Vs.

[0281] Certain embodiments of theranostic methods involve the use of diagnostic forms of radiotracers (e.g., *Cu for PET). 61 Cu, or *Cu is the SPECT67 Cu) to allow visualization of therapeutic target expression in vivo using companion imaging before switching to a radiolabeled therapeutic counterpart, e.g., *Cu is 64Cu or 67 It is Cu.

[0282] In certain embodiments, theranostic methods include: (a) As described herein 61 administering to a subject an effective amount of a compound containing a Cu radionuclide or a pharmaceutical composition containing the same; (b) generating one or more images of the subject (e.g., of a particular region or portion of the subject's body); (c) as described herein 67 administering to the subject an effective amount of a compound containing a Cu radionuclide or a pharmaceutical composition containing the same, wherein the compounds of steps (a) and (c) differ only in the identity of the radioisotope.

[0283] In certain embodiments, the compound described herein administered in step (a) 61 The amount of the compound containing a Cu radionuclide or pharmaceutical composition containing the same is effective to generate one or more images of the subject (i.e., a "detectably effective amount"). In certain embodiments, the amount of the compound or pharmaceutical composition containing the Cu radionuclide administered in step (a) described herein is effective to generate one or more images of the subject (i.e., a "detectably effective amount"). 61 The amount of the compound containing the Cu radionuclide or pharmaceutical composition containing same is effective for diagnosing the presence or absence of a disease (ie, a "diagnostically effective amount").

[0284] In certain embodiments, the method further comprises: acquiring, via one or more images of the subject, a body image of the subject; 61 and determining the presence or absence of a disease in the subject based on the presence or absence of localization of the Cu radionuclide. If the subject is not determined to have a disease, step (c) of the method is not performed.

[0285] In certain embodiments, the method further comprises administering to the subject in step (c) a compound described herein. 67In certain embodiments, the method further comprises calculating an effective therapeutic amount of a compound comprising a Cu radionuclide, as described herein, for administration to the subject in step (c). 67 The method includes calculating an effective therapeutic dose of a compound containing a Cu radionuclide.

[0286] In certain embodiments, the compound described herein administered in step (c) 67 The amount of the compound containing the Cu radionuclide or pharmaceutical composition containing same is therapeutically effective (ie, a "therapeutically effective amount") to treat the disease in question.

[0287] In certain embodiments, theranostic methods include: (a) As described herein 61 generating one or more images of a subject (e.g., of a particular region or portion of the subject's body), comprising administering to the subject an effective amount of a compound comprising a Cu radionuclide or a pharmaceutical composition comprising the same; (b) on the subject's body via one or more images of the subject 61 determining the presence or absence of a disease in a subject based on the presence or absence of localization of Cu radionuclides; (c) if the presence of a disease in the subject is determined, 67 administering to the subject an effective amount of a compound containing a Cu radionuclide or a pharmaceutical composition containing the same, wherein the compounds of steps (a) and (c) differ only in the identity of the radionuclide.

[0288] 4.5. Method for producing the composition In certain embodiments, the methods for making compounds and compositions according to formulas X* and A* provided herein include: (a) a high-purity radioactive copper solution; (b) a compound provided herein, e.g., according to Formula X, e.g., Formula A, containing Cu; This includes combining.

[0289] In certain embodiments, the combining is carried out at elevated temperature (80-95°C) for a reaction time of 15 minutes. In certain embodiments, the combining is carried out at room temperature for a reaction time of 15 minutes. In certain embodiments, the combining is carried out at room temperature for a reaction time of 2-5 minutes. In certain of these embodiments, the combining is carried out in a suitable buffer (e.g., ammonium acetate buffer, 0.5 M, pH=8).

[0290] In certain embodiments, the uncomplexed portion of the reaction mixture 61 No further purification steps are required to remove Cu, allowing direct use of the compound formed.

[0291] 4.5.1. Radiolabeling Yield (Radiochemical Yield) Radiochemical yield is the amount of radioactivity in the product expressed as a percentage (%) of the starting radioactivity used in the process considered (e.g., synthesis, separation, etc.). Both amounts relate to the same radionuclide and must be decay-corrected to the same point in time before calculations are made (see also Appendix A). Under this definition, the radiochemical yield relates only to the radionuclide considered and includes all radionuclide-labeled compounds that may undergo the same reactions as the radionuclide of interest (e.g., 68 in Ga preparations 68 It should be understood that this does not include Ge). A "radiochemical yield" calculated using decay-corrected radioactivity values ​​of the product and starting compounds is identical to the concept of "chemical yield." Logically, the reference time for decay correction must be the same to describe a particular reaction, whether chosen to be the end of radionuclide production, the end of bombardment, the start of synthesis, the end of synthesis, or any other convenient reference time point.

[0292] In certain embodiments, the compositions of the present disclosure are characterized by a radiolabeling yield at the end of labeling of 80% or greater. In further embodiments, the compositions are characterized by a radiolabeling yield of 95% or greater. In further embodiments, the compositions are characterized by a radiolabeling yield of 95% or greater at room temperature.

[0293] In certain embodiments, provided compositions are characterized by a radiolabeling yield of greater than 85%, e.g., greater than 85.5%, greater than 86.0%, greater than 86.5%, greater than 87.0%, greater than 87.5%, greater than 88.0%, greater than 88.5%, greater than 89.0%, greater than 89.5%, greater than 90.0%, greater than 90.5%, greater than 91.0%, greater than 91.5%, greater than 92.0%, greater than 92.5%, greater than 93.0%, greater than 93.5%, greater than 94.0%, greater than 94.5%, greater than 95.0%, greater than 95.5%, greater than 96.0%, greater than 96.5%, greater than 97.0%, greater than 97.5%, greater than 98.0%, greater than 98.5%, greater than 99.0%, or greater than 99.5%. In certain embodiments, compositions are characterized by a radiolabeling yield of greater than 90%. In certain embodiments, the composition is characterized by a radiolabeling yield of greater than 92%. In certain embodiments, the composition is characterized by a radiolabeling yield of greater than 95%.

[0294] 4.5.2. Characteristics of the Radionuclide Starting Material 60 Cu, 61 Cu, 62 Cu, 64 Cu and 67 High-purity compositions containing one or more copper radionuclides, Cu*, such as Cu, are produced using particle accelerators such as medical cyclotrons by deuteron, proton, or alpha particle bombardment of a target coin comprising a high-purity Nb backing and a target coating containing stable nickel or zinc isotopes. For example, a method for preparing high-purity compositions containing copper radionuclides is described in U.S. Provisional Patent Application No. 63 / 409,684, filed September 23, 2022, which is incorporated herein by reference in its entirety.

[0295] 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 or greater, 5M or greater, or 6M or greater.

[0296] In various embodiments, the radionuclide composition has a radionuclide purity of 95.0% or greater at the end of synthesis (EOB+2 hours). In certain embodiments, the high purity composition comprises: 6xCu radionuclides, e.g. 61 Cu, 64 Cu or 67 In certain embodiments, the high purity composition is suitable for use as, for example, a therapeutic agent. 64 In another embodiment, the high purity composition comprises 67 In certain embodiments, the high purity composition is for use as a radiotracer, e.g., in diagnostic imaging. 61 Contains Cu.

[0297] In various embodiments, the high purity composition is 61 It contains Cu, and the radionuclide purity at the end of synthesis is 97.0% or more.

[0298] In certain embodiments, 61 Cu, 64 Cu or 67 Cu, especially 61 Radionuclide compositions containing Cu, e.g., high purity radionuclides, are characterized by one or more of the following purity requirements: 110m Ag ≤ 0.1 Bq / g; 108m Ag ≤ 0.1 Bq / g; and 109 Cd≦0.1 Bq / g.

[0299] Considering the radioactive cobalt impurity, 64 The Ni(p,α) reaction is 61 Co(t 1 / 2 =1.649h) and other radioactive cobalt impurities (e.g., 55 Co) arise primarily from small amounts of other (A≠64) Ni isotopes in the isotopically enriched starting material. 61 In the context of Cu, among other reactions for other Ni isotopes, the main 61 Ni(p, α) and 60 The Ni(d,α) reaction is a long-lived 58 Co(t 1 / 2 =70.86d), 61 0.05% and 0.11% compared to Cu, respectively 58Co relative activity. Therefore, efficient purification of radionuclide compositions from radioactive cobalt by-products requires: 61 It may prove even more important in the context of Cu purification. 61 When considering the QC of Cu, Section 2.6 of the IAEA Radioisotopes and Radiopharmaceuticals Reports No. 1 [International Atomic Energy Agency, Cyclotron-Produced Radionuclides: Novel Positron Emitters for Medical Use: 64 Cu and 124 I(INTERNATIONAL ATOMIC ENERGY AGENCY,Cyclotron produced radionuclides:Emerging positron emitters for medical applications: 64 Cu and 124 I) Radioisotopes and Radiopharmaceuticals Reports 1, IAEA, Vienna (2016) 63, the entire contents of which are incorporated herein by reference. 64 The Cu radionuclide purity and molar activity are presented in great detail.

[0300] In certain embodiments, the high purity radionuclide composition is natural nickel or 60 via deuteron irradiation of Ni, or 61 The composition is produced via proton irradiation of Ni and includes one or more of the following: 56 Co≦1500Bq / g; 57 Co≦100Bq / g; 58 Co≦15000Bq / g; and 60 Co≦15Bq / g.

[0301] In certain embodiments, the high purity radionuclide composition is natural nickel or 60 via deuteron irradiation of Ni, or61 The composition is produced via proton irradiation of Ni and includes two or more of the following: 56 Co≦1500Bq / g; 57 Co≦100Bq / g; 58 Co≦15000Bq / g; 60 Co ≤ 15 Bq / g; and / or Have two or more of the following: 110m Ag ≤ 1 Bq / g; 108m Ag ≤ 1 Bq / g; and 109 Cd≦1Bq / g.

[0302] In certain embodiments, the high purity radionuclide composition is natural nickel or 60 via deuteron irradiation of Ni, or 61 The composition is produced via proton irradiation of Ni, the radionuclide is not a Cu radionuclide, and the composition includes one or more of the following: 110m Ag ≤ 0.1 Bq / g; 108m Ag ≤ 0.1 Bq / g; and 109 Cd≦0.1 Bq / g.

[0303] 4.5.2.1 Specific activity of radionuclides For producing the pharmaceutical composition of the present disclosure 61

[0039] provides specific activity measurements of the Cu]CuCl starting material. Methods for determining specific activity are known in the art.

[0304] In certain embodiments, provided compositions are characterized by a specific activity of 0.5 GBq / mg or greater, e.g., 1 GBq / mg or greater, 1.5 GBq / mg or greater, 2.0 GBq / mg or greater, 3.0 GBq / mg or greater, 4.0 GBq / mg or greater, 5.0 GBq / mg or greater, 6.0 GBq / mg or greater, 7.0 GBq / mg or greater, 8.0 GBq / mg or greater, 9.0 GBq / mg or greater, or 10.0 GBq / mg or greater.

[0305] In certain embodiments, the specific activity of the compositions provided herein is 0.5-10.0 GBq / mg, e.g., 1.0-10.0 GBq / mg, 2.0-10.0 GBq / mg, 3.0-10.0 GBq / mg, 4.0-10.0 GBq / mg, 5.0-10.0 GBq / mg, 6.0-10.0 GBq / mg, 7.0-10.0 GBq / mg, 8.0-10.0 GBq / mg, 9.0-10.0 GBq / mg, 0.5-5.0 GBq / mg, 1.0-5.0 GBq / mg, 2.0-5.0 GBq / mg, 3.0-5.0 GBq / mg, or 4.0-5.0 GBq / mg.

[0306] In certain embodiments, the specific activity of the compositions provided herein is between 0.5 and 1.9 GBq / mg, between 0.55 and 1.85 GBq / mg, between 0.6 and 1.8 GBq / mg, between 0.65 and 1.75 GBq / mg, between 0.7 and 1.7 GBq / mg, between 0.75 and 1.65 GBq / mg, between 0.8 and 1.6 GBq / mg, between 0.85 and 1.55 GBq / mg, between 0.9 and 1. ... 5~1.45GBq / mg, 1~1.4GBq / mg, 1.05~1.35GBq / mg, 1.1~1.3GBq / mg, 1.15~1.25GBq / mg, 0.6~1.3GBq / m g, 0.65~1.25GBq / mg, 0.7~1.2GBq / mg, 0.75~1.15GBq / mg, 0.8~1.1GBq / mg or 0.85~1.05GBq / mg.

[0307] In certain embodiments, the specific activity of the compositions provided herein is at least 0.5 GBq / mg, e.g., 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.

[0308] In certain embodiments, the specific activity of the compositions provided herein is between 0.5 GBq / mg and 10.0 GBq / mg, e.g., between 1.0 GBq / mg and 10.0 GBq / mg, 2.0 GBq / mg and 10.0 GBq / mg, 3.0 GBq / mg and 10.0 GBq / mg, 4.0 GBq / mg and 10.0 GBq / mg, 5.0 GBq / mg and 10.0 GBq / mg, 6.0 GBq / mg and 10.0 GBq / mg. q / mg, 7.0GBq / mg to 10.0GBq / mg, 8.0GBq / mg to 10.0GBq / mg, 9.0GBq / mg to 10.0GBq / mg, 0.5GBq / mg to 5.0GBq / mg, 1.0GBq / mg to 5.0GBq / mg, 2.0GBq / mg to 5.0GBq / mg, 3.0GBq / mg to 5.0GBq / mg, or 4.0GBq / mg to 5.0GBq / mg.

[0309] In certain embodiments, the specific activity is 0.5GBq / mg to 1.9GBq / mg, 0.55GBq / mg to 1.85GBq / mg, 0.6GBq / mg to 1.8GBq / mg, 0.65GBq / mg to 1.75GBq / mg, 0.7GBq / mg to 1.7 GBq / mg, 0.75GBq / mg~1.65GBq / mg, 0.8GBq / mg~1.6GBq / mg, 0.85GBq / mg~1.55GBq / mg, 0.9GBq / mg~1.5GBq / mg, 0.95GBq / mg~1.45GBq / m Compositions provided herein as 1 GBq / mg to 1.4 GBq / mg, 1.05 GBq / mg to 1.35 GBq / mg, 1.1 GBq / mg to 1.3 GBq / mg, 1.15 GBq / mg to 1.25 GBq / mg, 0.6 GBq / mg to 1.3 GBq / mg, 0.65 GBq / mg to 1.25 GBq / mg are characterized by a specific activity of 0.7 to 1.2 GBq / mg, 0.75 to 1.15 GBq / mg, 0.8 to 1.1 GBq / mg, or 0.85 GBq / mg to 1.05 GBq / mg.

[0310] In certain embodiments, the specific activity of the compositions provided herein is between 0.7 GBq / mg and 1.2 GBq / mg, between 0.75 GBq / mg and 1.15 GBq / mg, between 0.8 GBq / mg and 1.1 GBq / mg, or between 0.85 GBq / mg and 1.05 GBq / mg.

[0311] In certain embodiments, provided compositions are characterized by a specific activity of 0.5 GBq / mg or greater, e.g., 1 GBq / mg or greater, 1.5 GBq / mg or greater, 2.0 GBq / mg or greater, 3.0 GBq / mg or greater, 4.0 GBq / mg or greater, 5.0 GBq / mg or greater, 6.0 GBq / mg or greater, 7.0 GBq / mg or greater, 8.0 GBq / mg or greater, 9.0 GBq / mg or greater, or 10.0 GBq / mg or greater.

[0312] In certain embodiments, the specific activity of the compositions provided herein is 0.5-10.0 GBq / mg, e.g., 1.0-10.0 GBq / mg, 2.0-10.0 GBq / mg, 3.0-10.0 GBq / mg, 4.0-10.0 GBq / mg, 5.0-10.0 GBq / mg, 6.0-10.0 GBq / mg, 7.0-10.0 GBq / mg, 8.0-10.0 GBq / mg, 9.0-10.0 GBq / mg, 0.5-5.0 GBq / mg, 1.0-5.0 GBq / mg, 2.0-5.0 GBq / mg, 3.0-5.0 GBq / mg, or 4.0-5.0 GBq / mg.

[0313] In certain embodiments, the specific activity of the compositions provided herein is between 0.5 and 1.9 GBq / mg, between 0.55 and 1.85 GBq / mg, between 0.6 and 1.8 GBq / mg, between 0.65 and 1.75 GBq / mg, between 0.7 and 1.7 GBq / mg, between 0.75 and 1.65 GBq / mg, between 0.8 and 1.6 GBq / mg, between 0.85 and 1.55 GBq / mg, between 0.9 and 1. ... 5~1.45GBq / mg, 1~1.4GBq / mg, 1.05~1.35GBq / mg, 1.1~1.3GBq / mg, 1.15~1.25GBq / mg, 0.6~1.3GBq / m g, 0.65~1.25GBq / mg, 0.7~1.2GBq / mg, 0.75~1.15GBq / mg, 0.8~1.1GBq / mg or 0.85~1.05GBq / mg.

[0314] In certain embodiments, the specific activity of the compositions provided herein is at least 0.5 GBq / mg, e.g., 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.

[0315] In certain embodiments, the specific activity of the compositions provided herein is between 0.5 GBq / mg and 10.0 GBq / mg, e.g., between 1.0 GBq / mg and 10.0 GBq / mg, 2.0 GBq / mg and 10.0 GBq / mg, 3.0 GBq / mg and 10.0 GBq / mg, 4.0 GBq / mg and 10.0 GBq / mg, 5.0 GBq / mg and 10.0 GBq / mg, 6.0 GBq / mg and 10.0 GBq / mg. q / mg, 7.0GBq / mg to 10.0GBq / mg, 8.0GBq / mg to 10.0GBq / mg, 9.0GBq / mg to 10.0GBq / mg, 0.5GBq / mg to 5.0GBq / mg, 1.0GBq / mg to 5.0GBq / mg, 2.0GBq / mg to 5.0GBq / mg, 3.0GBq / mg to 5.0GBq / mg, or 4.0GBq / mg to 5.0GBq / mg.

[0316] In certain embodiments, the specific activity is 0.5GBq / mg to 1.9GBq / mg, 0.55GBq / mg to 1.85GBq / mg, 0.6GBq / mg to 1.8GBq / mg, 0.65GBq / mg to 1.75GBq / mg, 0.7GBq / mg to 1.7 GBq / mg, 0.75GBq / mg~1.65GBq / mg, 0.8GBq / mg~1.6GBq / mg, 0.85GBq / mg~1.55GBq / mg, 0.9GBq / mg~1.5GBq / mg, 0.95GBq / mg~1.45GBq / m Compositions provided herein as 1 GBq / mg to 1.4 GBq / mg, 1.05 GBq / mg to 1.35 GBq / mg, 1.1 GBq / mg to 1.3 GBq / mg, 1.15 GBq / mg to 1.25 GBq / mg, 0.6 GBq / mg to 1.3 GBq / mg, 0.65 GBq / mg to 1.25 GBq / mg are characterized by a specific activity of 0.7 to 1.2 GBq / mg, 0.75 to 1.15 GBq / mg, 0.8 to 1.1 GBq / mg, or 0.85 GBq / mg to 1.05 GBq / mg.

[0317] In certain embodiments, the specific activity of the compositions provided herein is between 0.7 GBq / mg and 1.2 GBq / mg, between 0.75 GBq / mg and 1.15 GBq / mg, between 0.8 GBq / mg and 1.1 GBq / mg, or between 0.85 GBq / mg and 1.05 GBq / mg.

[0318] In certain embodiments, provided compositions are characterized by a specific activity of 0.5 GBq / μg or greater, e.g., 1 GBq / μg or greater, 1.5 GBq / μg or greater, 2.0 GBq / μg or greater, 3.0 GBq / μg or greater, 4.0 GBq / μg or greater, 5.0 GBq / μg or greater, 6.0 GBq / μg or greater, 7.0 GBq / μg or greater, 8.0 GBq / μg or greater, 9.0 GBq / μg or greater, or 10.0 GBq / μg or greater.

[0319] In certain embodiments, the specific activity of the compositions provided herein is 0.5-10.0 GBq / μg, e.g., 1.0-10.0 GBq / μg, 2.0-10.0 GBq / μg, 3.0-10.0 GBq / μg, 4.0-10.0 GBq / μg, 5.0-10.0 GBq / μg, 6.0-10.0 GBq / μg, 7.0-10.0 GBq / μg, 8.0-10.0 GBq / μg, 9.0-10.0 GBq / μg, 0.5-5.0 GBq / μg, 1.0-5.0 GBq / μg, 2.0-5.0 GBq / μg, 3.0-5.0 GBq / μg, or 4.0-5.0 GBq / μg.

[0320] In certain embodiments, the specific activity of the compositions provided herein is between 0.5 and 1.9 GBq / μg, between 0.55 and 1.85 GBq / μg, between 0.6 and 1.8 GBq / μg, between 0.65 and 1.75 GBq / μg, between 0.7 and 1.7 GBq / μg, between 0.75 and 1.65 GBq / μg, between 0.8 and 1.6 GBq / μg, between 0.85 and 1.55 GBq / μg, between 0.9 and 1. ... 5~1.45GBq / μg, 1~1.4GBq / μg, 1.05~1.35GBq / μg, 1.1~1.3GBq / μg, 1.15~1.25GBq / μg, 0.6~1.3GBq / μg g, 0.65-1.25GBq / μg, 0.7-1.2GBq / μg, 0.75-1.15GBq / μg, 0.8-1.1GBq / μg, or 0.85-1.05GBq / μg.

[0321] In certain embodiments, the specific activity of the compositions provided herein is at least 0.5 GBq / μg, e.g., 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.

[0322] In certain embodiments, the specific activity of the compositions provided herein is between 0.5 GBq / μg and 10.0 GBq / μg, e.g., between 1.0 GBq / μg and 10.0 GBq / μg, 2.0 GBq / μg and 10.0 GBq / μg, 3.0 GBq / μg and 10.0 GBq / μg, 4.0 GBq / μg and 10.0 GBq / μg, 5.0 GBq / μg and 10.0 GBq / μg, 6.0 GBq / μg and 10.0 GBq / μg. q / μg, 7.0GBq / μg~10.0GBq / μg, 8.0GBq / μg~10.0GBq / μg, 9.0GBq / μg~10.0GBq / μg, 0.5GBq / μg~5.0GBq / μg , 1.0GBq / μg~5.0GBq / μg, 2.0GBq / μg~5.0GBq / μg, 3.0GBq / μg~5.0GBq / μg, or 4.0GBq / μg~5.0GBq / μg.

[0323] In certain embodiments, the specific activity is 0.5GBq / μg to 1.9GBq / μg, 0.55GBq / μg to 1.85GBq / μg, 0.6GBq / μg to 1.8GBq / μg, 0.65GBq / μg to 1.75GBq / μg, 0.7GBq / μg to 1.7 GBq / μg, 0.75GBq / μg~1.65GBq / μg, 0.8GBq / μg~1.6GBq / μg, 0.85GBq / μg~1.55GBq / μg, 0.9GBq / μg~1.5GBq / μg, 0.95GBq / μg~1.45GBq / μg Compositions provided herein as 0.6 GBq / μg to 1.3 GBq / μg, 0.65 GBq / μg to 1.25 GBq / μg, 1 GBq / μg to 1.4 GBq / μg, 1.05 GBq / μg to 1.35 GBq / μg, 1.1 GBq / μg to 1.3 GBq / μg, 1.15 GBq / μg to 1.25 GBq / μg, 0.6 GBq / μg to 1.3 GBq / μg, 0.65 GBq / μg to 1.25 GBq / μg are characterized by a specific activity of 0.7 to 1.2 GBq / μg, 0.75 to 1.15 GBq / μg, 0.8 to 1.1 GBq / μg, or 0.85 GBq / μg to 1.05 GBq / μg.

[0324] In certain embodiments, the specific activity of the compositions provided herein is between 0.7 GBq / μg and 1.2 GBq / μg, between 0.75 GBq / μg and 1.15 GBq / μg, between 0.8 GBq / μg and 1.1 GBq / μg, or between 0.85 GBq / μg and 1.05 GBq / μg.

[0325] 4.5.2.2 Chemical purity In certain embodiments, radionuclide compositions are characterized for "chemical purity," understood herein as the molar percentage of the identified or desired radionuclide relative to all metals in the sample. Radionuclide compositions prepared by the methods disclosed herein exhibit high chemical purity, which facilitates the production of radiopharmaceuticals with high radiochemical purity. Radiochemical purity, as understood herein, is the ratio or percentage of reactivity from the desired radionuclide in the radiopharmaceutical relative to the total radioactivity of the sample containing the radiopharmaceutical. Non-radioactive isotopes of metals ("cold" metals) do not contribute to the total radioactivity of the sample, but can compete with the desired radionuclide for inclusion in the radiopharmaceutical, e.g., compete for chelation sites on the radiopharmaceutical.

[0326] In certain embodiments, radionuclide compositions according to the present disclosure have a chemical purity of 99.0% molar or greater. In certain embodiments, the radionuclide compositions are prepared according to the methods provided herein.

[0327] In certain embodiments, the radionuclide composition is an aqueous solution and is characterized by one or more of the following: e ≤ 2 μg / L; 69 Cu and 65 Cu combined ≤1 μg / L; Zn(II) ≤ 2 μg / L; Sn(IV) ≤ 0.01 μg / L; Ti(IV) ≤ 0.01 μg / L; Al(III) ≤ 2 μg / L; As ≤ 1 μg / L; Ni ≤ 1 μg / L; Any of Cr, Cd, Co, and Y ≤ 0.1 μg / mL.

[0328] In certain embodiments, the radionuclide composition comprises Fe≦2 μg / L. In certain embodiments, the presence of iron 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, / L or less, 1.5μg / L or less, 1.4μg / L or less, 1.3μg / L or less, 1.2μg / L or less, 1.1μg / L or less, 1μg / L or less, 0.9μg / L or less, 0.8μg / L L or less, 0.7μg / L or less, 0.6μg / L or less, 0.5μg / L or less, 0.4μg / L or less, 0.3μg / L or less, 0.2μg / L or less, or 0.1μg / L or less.

[0329] In certain embodiments, the radionuclide composition is characterized by comprising Cu(cold)≦1 μg / L. In certain embodiments, Cu(cold) is present at or below 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.

[0330] In certain embodiments, the radionuclide composition is characterized by comprising Ni≦1 μg / L. In certain embodiments, the presence of nickel 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. Bottom, 2.3μg / L or less, 2.2μg / L or less, 2.1μg / L or less, 2μg / L or less, 1.9μg / L or less, 1.8μg / L or less, 1.7μg / L or less, 1.6μg / L or less, 1.5μg / L or less, 1.4μg / L or less, 1.3μg / L or less, 1.2μg / L L or less, 1.1 μg / L or less, 1 μg / L or less, 0.9 μg / L or less, 0.8 μg / L or less, 0.7 μg / L or less, 0.6 μg / L or less, 0.5 μg / L or less, 0.4 μg / L or less, 0.3 μg / L or less, 0.2 μg / L or less, or 0.1 μg / L or less.

[0331] In certain embodiments, the radionuclide composition is as described above, further characterized by one or more of a radioactivity concentration of 0.60-0.66 GBq / mL at EoB+2 hours, a molar radioactivity of 10-100 MBq / nmol at EoB+2 hours, and a radioactivity of greater than 500 MBq at EoB+2 hours. One embodiment is as described above, further characterized by one or more of a radioactivity concentration of greater than 25 MBq / mL at EoB+2 hours, a molar radioactivity of 10-150 MBq / nmol at EoB+2 hours, and a radioactivity of greater than 150 MBq at EoB+2 hours.

[0332] One embodiment as described above is further characterized by one or more of a radioactivity concentration of 0.60-0.66 GBq / mL at EoB+2 hours, a molar radioactivity of 10-100 MBq / nmol at EoB+2 hours, and a radioactivity at end of synthesis of greater than 500 MBq.

[0333] 4.5.3. Radioactivity concentration The radioactivity concentration is [61 Cu]CuCl2 is the total amount of radioactivity per unit volume of starting material.

[0334] In certain embodiments, 0.5 GBq / mL or more, e.g., 1 GBq / mL or more, 1.5 GBq / mL or more, 2.0 GBq / mL or more, 3.0 GBq / mL or more, 4.0 GBq / mL or more, 5.0 GBq / mL or more, 6.0 GBq / mL or more, 7.0 GBq / mL or more, 8.0 GBq / mL or more, 9.0 GBq / mL or more, or 10.0 GBq / mL or more.

[0335] In certain embodiments, provided compositions are characterized by a radioactivity concentration of 0.5 to 10.0 GBq / mL, e.g., 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.

[0336] In certain embodiments, the compositions provided comprise a concentration of 0.5-1.9 GBq / mL, 0.55-1.85 GBq / mL, 0.6-1.8 GBq / mL, 0.65-1.75 GBq / mL, 0.7-1.7 GBq / mL, 0.75-1.65 GBq / mL, 0.8-1.6 GBq / mL, 0.85-1.55 GBq / mL, 0.9-1.5 GBq / mL, 0.95-1.45 GBq They are characterized by radioactivity concentrations of 0.6-1.3 GBq / mL, 0.65-1.25 GBq / mL, 0.7-1.2 GBq / mL, 0.75-1.15 GBq / mL, 0.8-1.1 GBq / mL, or 0.85-1.05 GBq / mL.

[0337] In certain embodiments, provided pharmaceutical compositions are characterized by a radioactivity concentration of 0.3 to 0.75 GBq / mL.

[0338] In certain embodiments, the radioactivity concentration of the resulting pharmaceutical composition is diluted 3 to 10 times, so long as the radioactivity concentration is 8 MBq / mL or greater. In certain embodiments, the provided compositions are characterized by a radioactivity 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. 4.6. List of Embodiments Enumerated Group A of Embodiments Embodiment 1a: The compound is a compound of formula X: [ka] or a pharmaceutically acceptable salt thereof; the chelating moiety is NODAGA; *Cu is 61 Cu or 67 Cu; L is [ka] and; V is a targeting moiety that binds to PSMA; n is 1; m is 1; Compounds where p is 1. Embodiment 1b: The compound is a compound of formula X: [ka] or a pharmaceutically acceptable salt thereof; the chelating moiety is NODAGA; *Cu is 61 Cu, 62 Cu, 64Cu and 67 a copper radionuclide selected from Cu; L is [ka] and; V is a targeting moiety that binds to PSMA; n is 1; m is 1; The compound of any of the preceding embodiments, wherein p is 1. Embodiment 1. The compound is a compound of formula 10: [ka] or a pharmaceutically acceptable salt thereof; The compound of any of the preceding embodiments, wherein V comprises a targeting moiety that binds to PSMA. Embodiment 2. The compound of any of the preceding embodiments, wherein V comprises a means for binding to PSMA. Embodiment 3.V has the structure: [ka] The compound of any of the preceding embodiments, comprising: Embodiment 4. The compound is a compound of the following structure: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 5. The compound is a compound of the following structure: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 6a: The compound is a compound of formula X*: [ka] or a pharmaceutically acceptable salt thereof; the chelating moiety is NODAGA; *Cu is 61 Cu, 62 Cu, 64 Cu and 67 a copper radionuclide selected from Cu; L is [ka] and; V is a targeting moiety that binds to PSMA; n is 1; m is 1; The compound of any of the preceding embodiments, wherein p is 1. Embodiment 6. The compound of any of the previous embodiments comprising a copper atom chelated by the compound of embodiment 1, wherein the compound has the structure of formula 10*: [ka] or a pharmaceutically acceptable salt thereof; *Cu is 61 Cu, 62 Cu, 64 Cu and 67 The compound is a copper radionuclide selected from Cu. Embodiment 7. *Cu is 61 The compound of embodiment 6a or 6, wherein Cu. Embodiment 8. *Cu is 67 The compound of embodiment 6a or 6, wherein Cu. Embodiment 9.V has the structure: [ka] The compound of any of the preceding embodiments, comprising: Embodiment 10. The compound is a compound of the following structure: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 11. The compound is a compound of the following structure: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 12. The compound has the structure: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 13. The compound has the structure: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 14. A pharmaceutical composition comprising a compound according to any of the preceding embodiments and a pharmaceutically acceptable excipient, wherein the composition is molar radioactivity of 3 MBq / nmol or more; Radiochemical purity over 91%; radioactivity concentration of 8MBq / mL or more; The radionuclide purity of the compound at the end of synthesis (EoB+2 hours) is 95% or greater; and pH 4-7 A pharmaceutical composition characterized by one or more of the following: Embodiment 15. The composition of any of the preceding embodiments, wherein the composition is characterized by a molar radioactivity of 3 MBq / nmol or more, e.g., 10 MBq / nmol or more, 10-250 MBq / nmol, 20-250 MBq / nmol, 50-250 MBq / nmol, 50-200 MBq / nmol, 50-150 MBq / nmol, 50-100 MBq / nmol, 100-250 MBq / nmol, 100-150 MBq / nmol, 150-250 MBq / nmol, 150-200 MBq / nmol, or 200-250 MBq / nmol. Embodiment 16. The composition of any of the preceding embodiments, wherein the composition is characterized by a radiochemical purity of 91% or greater, e.g., 95% or greater, 95.5% or greater, 96% or greater, 96.5% or greater, 97% or greater, 97.5% or greater, 98% or greater, 98.5% or greater, 99% or greater, or 99.5% or greater. Embodiment 17. The composition of any of the preceding embodiments, wherein the composition is characterized by a radioactivity concentration of 8 MBq / mL or greater, e.g., 8-400 MBq / mL, 8-350 MBq / mL, 8-300 MBq / mL, 8-250 MBq / mL, 8-200 MBq / mL, 8-150 MBq / mL, 8-100 MBq / mL, 8-100 MBq / mL, 8-50 MBq / mL, 8-25 MBq / mL, or 8-15 MBq / mL. Embodiment 18. The composition of any of the preceding embodiments, wherein the composition is characterized by a radionuclide purity of the compound at the end of synthesis of 95% or greater, e.g., 95.5% or greater, 96% or greater, 96.5% or greater, 97% or greater, 97.5% or greater, 98% or greater, 98.5% or greater, 99% or greater, 99.1% or greater, 99.2% or greater, 99.3% or greater, 99.4% or greater, 99.5% or greater, 99.6% or greater, 99.7% or greater, 99.8% or greater, 99.9% or greater, or 99.99% or greater. Embodiment 19. The composition of any of the previous embodiments, wherein the composition is characterized in that the radioactive cobalt compound has a total radionuclide purity at the end of synthesis (EoB+2 hours) of 0.05% or less, e.g., 0.04% or less, 0.03% or less, 0.02% or less, or 0.01% or less. Embodiment 20. The composition of any of the preceding embodiments, wherein the composition is characterized by a pH of 4 to 7. Embodiment 21. A composition comprising a compound of any of the previous embodiments and a pharmaceutically acceptable excipient, wherein the composition is molar radioactivity of 20 MBq / nmol or more; Radiochemical purity over 91%; Radioactivity concentrations of 8 to 100 MBq / mL or more; The radionuclide purity of the compound at the end of synthesis (EoB+2 hours) is 95% or greater; and pH 4-7 A composition characterized by one or more of the following: Embodiment 22. The composition of any of the preceding embodiments, wherein the composition is characterized by a molar radioactivity of 20 MBq / nmol or more, e.g., 20-250 MBq / nmol, 50-250 MBq / nmol, 50-200 MBq / nmol, 50-150 MBq / nmol, 50-100 MBq / nmol, 100-250 MBq / nmol, 100-150 MBq / nmol, 150-250 MBq / nmol, 150-200 MBq / nmol, or 200-250 MBq / nmol. Embodiment 23. The composition of any of the preceding embodiments, wherein the composition is characterized by a radiochemical purity of 91% or greater, such as 95% or greater, 95.5% or greater, 96.0% or greater, 96.5% or greater, 97.0% or greater, 97.5% or greater, 98.0% or greater, 98.5% or greater, 99.0% or greater, or 99.5% or greater. Embodiment 24. The composition of any of the preceding embodiments, wherein the composition is characterized by a radioactivity concentration of 8 to 100 MBq / mL, for example 8 to 15 MBq / mL. Embodiment 25. The composition of any of the preceding embodiments, wherein the composition is characterized by a radionuclide purity of the compound at the end of synthesis of 95.0% or greater, e.g., 95.5% or greater, 96% or greater, 96.5% or greater, 97% or greater, 97.5% or greater, 98% or greater, 98.5% or greater, 99% or greater, 99.1% or greater, 99.2% or greater, 99.3% or greater, 99.4% or greater, 99.5% or greater, 99.6% or greater, 99.7% or greater, 99.8% or greater, or 99.9% or greater. Embodiment 26. The composition of any of the preceding embodiments, wherein the composition is characterized in that the total radionuclide purity of the radioactive cobalt compound at the end of synthesis (EoB+2 hours) is 0.05% or less, e.g., 0.04% or less, 0.03% or less, 0.02% or less, or 0.01% or less. Embodiment 27. A method for generating one or more images of an object, comprising: administering to a subject an effective amount of the composition of embodiment 14; generating one or more images of at least a portion of a subject's body; A method comprising: Embodiment 28. The method of embodiment 27, wherein the one or more images are generated using positron emission tomography (PET) or single photon emission computed tomography (SPECT). Embodiment 29. A method of treating cancer in a patient, comprising administering to the patient an effective amount of the composition of embodiment 21. Embodiment 30. (a) administering to a subject an effective amount of the composition of embodiment 14; (b) generating one or more images of at least a portion of the subject's body; (c) administering to a subject an effective amount of a composition comprising a compound according to any of the preceding embodiments; A treatment method comprising:

[0339] Enumeration Group B of Embodiments Embodiment 1a. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable excipient, wherein the compound is a compound of formula X*: [ka] or a pharmaceutically acceptable salt thereof, the chelating moiety is NODAGA; *Cu is 61 Cu, 62 Cu, 64 Cu and 67 a copper radionuclide selected from Cu; L is a linker moiety; V is a targeting moiety SST that binds to SSTR; n is 1; m is 1; and p is 1. Embodiment 1. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable excipient, wherein the compound is a compound of formula 20: [ka] or a pharmaceutically acceptable salt thereof, *Cu is 61 Cu, 62 Cu and 67 a copper radionuclide selected from Cu; L is a bond or linker moiety; A pharmaceutical composition wherein SST is a targeting moiety that binds to somatostatin receptors. Embodiment 2. The composition molar radioactivity of 3 MBq / nmol or more; Radiochemical purity over 91%; radioactivity concentration of 8MBq / mL or more; The radionuclide purity of the compound at the end of synthesis (EoB+2 hours) is 95% or greater; and pH 4-7 2. The composition of embodiment 1, characterized by one or more of: Embodiment 3. The composition of any of the preceding embodiments, wherein the composition is characterized by a molar radioactivity of 3 MBq / nmol or more, e.g., 10 MBq / nmol or more, 10-250 MBq / nmol, 20-250 MBq / nmol, 50-250 MBq / nmol, 50-200 MBq / nmol, 50-150 MBq / nmol, 50-100 MBq / nmol, 100-250 MBq / nmol, 100-150 MBq / nmol, 150-250 MBq / nmol, 150-200 MBq / nmol, or 200-250 MBq / nmol. Embodiment 4. The composition of any of the preceding embodiments, wherein the composition is characterized by a radiochemical purity of 91% or greater, e.g., 95% or greater, 95.5% or greater, 96% or greater, 96.5% or greater, 97% or greater, 97.5% or greater, 98% or greater, 98.5% or greater, 99% or greater, or 99.5% or greater. Embodiment 5. The composition of any of the preceding embodiments, wherein the composition is characterized by a radioactivity concentration of 8 MBq / mL or greater, e.g., 8-400 MBq / mL, 8-350 MBq / mL, 8-300 MBq / mL, 8-250 MBq / mL, 8-200 MBq / mL, 8-150 MBq / mL, 8-100 MBq / mL, 8-100 MBq / mL, 8-50 MBq / mL, 8-25 MBq / mL, or 8-15 MBq / mL. Embodiment 6. The composition of any of the preceding embodiments, wherein the composition is characterized by a radionuclide purity of the compound at the end of synthesis of 95% or greater, e.g., 95.5% or greater, 96% or greater, 96.5% or greater, 97% or greater, 97.5% or greater, 98% or greater, 98.5% or greater, 99% or greater, 99.1% or greater, 99.2% or greater, 99.3% or greater, 99.4% or greater, 99.5% or greater, 99.6% or greater, 99.7% or greater, 99.8% or greater, 99.9% or greater, or 99.99% or greater. Embodiment 7. The composition of any of the preceding embodiments, wherein the composition is characterized by a pH of 4 to 7. Embodiment 8. The composition of any of the preceding embodiments, wherein the SST comprises a means for binding to a somatostatin receptor. Embodiment 9. The SST has the structure: [ka] 2. The composition of any of the preceding embodiments, comprising: Embodiment 10. The SST has the structure: [ka] 2. The composition of any of the preceding embodiments, comprising: Embodiment 11. The compound is a compound of the following structure: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 12. The compound is a compound of the following structure: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 13. The compound is a compound of the following structure: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 14. The compound is a compound of the following structure: [ka] or a pharmaceutically acceptable salt thereof. Embodiment 15. A method for generating one or more images of an object, comprising: (a) administering to a subject an effective amount of the composition of embodiment 11; (b) generating one or more images of at least a portion of the subject's body; A method comprising: Embodiment 16. The method of embodiment 14, wherein the one or more images are generated using photon emission tomography (PET). Embodiment 17. The method of embodiment 14, wherein the one or more images are generated using single photon emission computed tomography (SPECT). Embodiment 18. A theranostic method comprising: (a) administering to a subject an effective amount of a first pharmaceutical composition, wherein the composition is according to embodiment 11; (b) generating one or more images of at least a portion of the subject's body; (c) administering to the subject an effective amount of a second pharmaceutical composition comprising a compound, wherein the compound is a compound of Formula 20 as defined in embodiment 1, or a pharmaceutically acceptable salt thereof; Theranostic methods, including: Enumerated Group C of Embodiments Embodiment 1. A pharmaceutical composition comprising a compound and a pharmaceutically acceptable excipient, wherein the compound is a compound of formula 30: [ka] R 1 is R a and; R 2 and R 3 are R a or together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring; R a independently for each occurrence, 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 5-9 heteroaryl, optionally substituted with one or more substituents selected from: —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is, for each occurrence, independently selected from: 1-10 Alkyl or C 3-10 is cycloalkyl; n is an integer from 1 to 20; m is an integer from 1 to 20; *Cu is 61 Cu, 62 Cu, 64 Cu and 67 a copper radionuclide selected from Cu; or a pharmaceutically acceptable salt thereof; The composition comprises: molar radioactivity of 3 MBq / nmol or more; Radiochemical purity over 91%; Radioactivity concentration of 8 MBq / mL or greater; and Radionuclide purity of the compound at the end of synthesis (EoB+2 hours) is 95% or more A pharmaceutical composition characterized by one or more of the following: Embodiment 2.R 1 is methyl or H. Embodiment 3.R 2 is H and R 3 is H. Embodiment 4.R 2 and R 3 together with the nitrogen atom to which they are attached and C 2-9 The composition of embodiment 1 or 2, wherein the compound forms a heterocycle. Embodiment 5.C 2-9 The composition of embodiment 4, wherein the heterocycle is a 6-membered heterocycle selected from piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane. Embodiment 6. The radionuclide is 61 Cu and 67 6. The composition of any one of embodiments 1 to 5, wherein Cu is selected from: Embodiment 7. The composition of any one of embodiments 1-6, wherein the compound is a compound of formula 30a or 30b: [ka] [ka] Embodiment 8.R 1 is H or methyl. Embodiment 9. The radionuclide is 61 Cu and 67 The composition of embodiment 7 or 8, wherein the hydroxyl group is selected from Cu. Embodiment 10. The compound is [Table 6-1] [Table 6-2] or a pharmaceutically acceptable salt thereof. Embodiment 11. The composition of any one of embodiments 1 to 10, wherein the molar radioactivity of the composition is 3 MBq / nmol or more, e.g., 10 MBq / nmol or more, 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. Embodiment 12. The composition of any one of embodiments 1-11, wherein the radiochemical purity of the composition is 91% or greater, e.g., 95% or greater, 95.5% or greater, 96% or greater, 96.5% or greater, 97% or greater, 97.5% or greater, 98% or greater, 98.5% or greater, 99% or greater, or 99.5% or greater. Embodiment 13. The composition of any one of embodiments 1 to 12, wherein the radioactivity concentration of the composition is 8 MBq / mL or more, e.g., 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. Embodiment 14. The composition of any one of embodiments 1-13, wherein the composition is characterized by a radionuclide purity of the compound at the end of synthesis of 95% or greater, e.g., 95.5% or greater, 96% or greater, 96.5% or greater, 97% or greater, 97.5% or greater, 98% or greater, 98.5% or greater, 99% or greater, 99.1% or greater, 99.2% or greater, 99.3% or greater, 99.4% or greater, 99.5% or greater, 99.6% or greater, 99.7% or greater, 99.8% or greater, 99.9% or greater, or 99.99% or greater. Embodiment 15. The composition of any one of embodiments 1 to 14, wherein the composition has a pH of 4 to 7. Embodiment 16. A method for generating one or more images of an object, comprising: Radionuclides 61 Administering to a subject an effective amount of the composition of any one of embodiments 1-15, wherein the composition is Cu; generating one or more images of at least a portion of a subject's body; A method comprising: Embodiment 17. The method of embodiment 16, wherein the one or more images are generated using positron emission tomography (PET), PET-computed tomography (PET-CT), or single photon emission computed tomography (SPECT). Embodiment 18. The method of embodiment 16 or 17, wherein the one or more images are generated using PET-CT. Embodiment 19. A method of treating a disease in a patient in need thereof, wherein the radionuclide 67 Administering to a patient an effective amount of the composition of embodiment 1, wherein the composition is Cu. Embodiment 20. The method of embodiment 19, wherein the disease is selected from cancer, an inflammatory disease, an infectious disease, and an immune disease. Embodiment 21 The method of embodiment 19 or 20, wherein the disease is cancer. 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 carcinoma, esophageal cancer, hypopharyngeal carcinoma, nasopharyngeal carcinoma, laryngeal carcinoma, myeloma cells, bladder carcinoma, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumors, oncogenetic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical carcinoma, and prostate cancer. Embodiment 23. A theranostic method comprising: (a) administering to a subject an effective amount of a first pharmaceutical composition, the composition being according to embodiment 1, wherein the radionuclide is 61 Cu; (b) generating one or more images of the object; (c) administering to the subject an effective amount of a second pharmaceutical composition comprising a compound, wherein the compound is a compound of Formula 30: [ka] During the ceremony, R 1 is R a and; R 2 and R 3 are R a or together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring; R a independently for each occurrence, 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 5-9 heteroaryl, optionally substituted with one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is independently for each occurrence C 1-10 Alkyl or C 3-10 is cycloalkyl; n is an integer from 1 to 20; m is an integer from 1 to 20; *Cu is 67 Cu; or a pharmaceutically acceptable salt thereof. Theranostic methods, including: Embodiment 24: (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, (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, (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 (d) the compound of the first pharmaceutical composition is 61 [Cu]Cu-NODAGA-F4, and the compound of the second pharmaceutical composition is 67 24. The method of embodiment 23, wherein the compound is [Cu]Cu-NODAGA-F4. Embodiment 25. Intracellular administration of a first compound in the body of a subject 61 25. The method of embodiment 23 or 24, further comprising determining the presence or absence of disease in the subject via one or more images of the subject based on the presence or absence of localization of the Cu radionuclide. Embodiment 26. The method of embodiment 25, wherein the disease is selected from cancer, an inflammatory disease, an infectious disease, and an immune disease. Embodiment 27. The method of any one of embodiments 23 to 27, wherein the one or more images are generated using positron emission tomography (PET), PET-computed tomography (PET-CT), or single photon emission computed tomography (SPECT). Embodiment 28. A method of making the composition of embodiment 1, comprising combining a high purity radioactive copper solution with a compound of formula 40: [ka] R 1 is R a and; R 2 and R 3 are R a or together with the nitrogen atom to which they are attached and C 2-9 Forming a heterocyclic ring; Ra independently for each occurrence, 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 5-9 heteroaryl, optionally substituted with one or more substituents selected from: —OH, —OR′, ═O, ═S, —SH, —SR′, —NH, —NHR′, —N(R′) , —NHCOR′, —NR′COR′, halogen, —CN, —COH, —COR′, —CHO, —COR′, —CONH, —CONHR′, —CON(R′) , —NO , —OP(O)(OH) , —SOH, —SOR′, —SOR′, and —SOR′; R′ is, for each occurrence, independently selected from: 1-10 Alkyl or C 3-10 is cycloalkyl; n is an integer from 1 to 20; m is an integer from 1 to 20; High purity radioactive copper solution 99% molar or greater chemical purity and / or: Fe ≤ 2 mg / L; 69 Cu and 65 Cu combined ≤1 mg / L; Zn ≤ 2 mg / L; Sn ≤ 0.01 mg / L; Ti ≤ 0.01 mg / L; Al ≤ 2 mg / L; As ≤ 1 mg / L; Ni ≤ 1 mg / L; Cr, Cd, Co and Y are less than 0.1 mg / mL A method characterized by one or more of the following: Embodiment 29. The high-purity radioactive copper solution is 61 29. The method of embodiment 28, wherein the HCl is HCl. 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 to 95°C. 5. Example Summary of experimental observations

[0340] Given the increasing clinical demand for PSMA-targeted PET imaging, 68 The generator that produced Ga-tracer (2–3 patient doses) had very limited manufacturing capacity. 18 F-labeled derivatives are an alternative, but this comes at the expense of facile chelator-based radiolabeling kits and the potential for therapeutic companions (theranostics), 18 This is an option not offered in F. Furthermore, 18 Pitfalls of the F-PSMA radiotracer raise concerns. 61 Cu can be produced at large scale in a cyclotron, allowing for kit-based radiolabeling and for a longer half-life 68 Ga or 18 It has a larger distribution radius than F. In addition, this allows for delayed imaging, which can result in improved image contrast without additional radiation burden to the patient compared to existing PSMA radiotracers.

[0341] As a proof of concept, 61 Cu was chelated to a targeting moiety (e.g., PSMA-I&T, SS analogs, or FAP inhibitors) via a chelator (e.g., NODAGA) and a linker moiety. The targeted chelator constructs were synthesized within minutes at room temperature. 61 Label with Cu and use a modular-assisted radiosynthesis or purification system ( 18 Used daily in F and often 68 A rapid and simple procedure for producing PET tracers was reported, without the need for expensive infrastructure such as that used for Ga radioactive tracers. 68 Ga, as opposed to a maximum of 1-3 doses) on-site by the radiopharmacist / practitioner on the working day 61 Allows additional flexibility to manufacture multiple (more than 3) patient doses from a single shipment of Cu.

[0342] Conjugation of constructs bearing the same targeting moiety (PSMA-I&T, somatostatin analogs or FAP inhibitors) via NODAGA chelators to therapeutic radionuclides of the same chemical element, i.e., beta-emitters, useful for radiotherapy. 67 It is possible to create a radioactive tracer containing Cu. Because it is the same chemical element, 67 Cu is 61 It is bound by a chelator and targeting moiety in exactly the same chemical manner as Cu. It is a chemically identical companion radiotracer for 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, and [ 67 Cu]Cu-NODAGA-F4, and [ 67 These therapeutic compounds have the same properties and systemic distribution as PET radiotracers, including antigen-targeted lesions. 67 Cu 177 Although it has a shorter half-life than Lu (t 1 / 2 67 Cu=2.6 days vs. 177 Lu = 6.7 days), the energies of the beta particles are very similar. Therefore, 67 Cu was expected to potentially better match the pharmacokinetics of the proposed tracer, potentially allowing for shorter time intervals between treatment cycles, and finally, to have a lower radiation burden for patients and better logistics regarding waste management in hospitals.

[0343] High purity [ 61 Cu]CuCl2 The relatively short half-life (t 1 / 2 68 Ga = 68 min; 18Due to their F = 110 min and physical properties, key challenges in the PET tracer industry remain a) image quality, b) reliability of supply and distribution of radiopharmaceuticals at low cost, and c) low radiation burden to the patient. 61 The particular advantages of using Cu are a) good image quality due to its physical properties (low mean positron energy) but also the possibility of delayed imaging, which is expected to improve diagnostic sensitivity due to spillover of radioactivity from the background and therefore improved image contrast; b) its relatively long half-life (t 1 / 2 61 Cu = 205.5 min), c) still ensures that the radiation burden on the patient is kept to a minimum. For use in radiopharmaceutical applications, e.g., as a positron emitter in PET tracers, at high activity concentrations and in high doses, [ 61 High purity in the form of Cu]CuCl2 61 This paper provides a possible explanation for a new process for producing Cu. 61 Cu, especially high purity 61 No Cu use was recorded.

[0344] Trace metals and cold copper 61 Chelators (e.g., NODAGA) compete with Cu to bind in this order: non-radioactive Cu(II) (i.e., stable isotopes) > Zn(II) > Fe(III) > Sn(IV) > Ti(IV) > Al(III). Competition with these trace metals and non-radioactive copper significantly reduces the radiolabeling yield and radiochemical purity of the tracer (see "Innovative Complexation Strategies for the Introduction of Short-lived PET Isotopes into Radiopharmaceuticals" (p. 105). Frequent sources of trace metals are the raw nickel metal powder itself, especially isotopically enriched nickel, reagents, and any metals in the equipment used, such as iron. Purification processes (ion exchange columns) can be used to remove non-radioactive (stable isotopes)69 Cu and 65 Removes most of the trace metals except for Cu (particularly relevant to Cu), which is desirable 61 One way to prevent non-radioactive copper contamination and the associated loss of chemical purity is to run a dissolved nickel feedstock (stable isotope) through the process and separate the non-radioactive copper from the nickel before plating (see Figure 8 for ICP-MS analysis). Table 4 shows the results of the ICP-MS analysis of non-radioactive copper on a niobium backing. nat Ni or 61 Either by Ni bombardment and the resulting impurity profile [ 61 Cu]CuCl2. [Table 7]

[0345] Radionuclide purity Radionuclide purity is important in radiopharmaceuticals because radionuclide impurities can increase the radiation dose received by the patient and potentially reduce the quality of any imaging procedures performed. For example, the presence of significant levels of other radionuclides can alter biodistribution. Radionuclide samples contain several contaminants that cause the manufacturing process or decay of the primary radioisotope. Radionuclide impurities can arise as a result of the manufacturing process; for example, in cyclotron-produced nuclides, 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 level of contamination allowed. These limits are defined by government agencies, for example in pharmacopoeial monographs, and vary depending on the physical decay characteristics of the radionuclide involved and the potential contaminants. Measurements of radionuclide purity can be performed with high resolution using gamma spectroscopy on samples long after bombardment. The radioactivity of long-lived isotopes can then be extrapolated to EoB, EoS, or even end of life. The high radioactivity emitted from long-lived radionuclide impurities significantly increases the cost and complexity of managing the disposal of all consumables that come into contact with the nuclide compositions.

[0346] Natural Nickel and 60 Deuteron irradiation of Ni and 61 Proton irradiation of Ni produces long-lived isotopes of cobalt: 56 Co, 57 Co, 58 Co and 60 Co is produced. 110m Ag, 108m Ag and 109 Other long-lived radionuclides, such as Cd, are produced by irradiation of commonly used silver backing materials and are dissolved together with the starting material during the purification process. Due to their long half-lives, the proportion of these radionuclides is 61 It increases over time compared to Cu, especially as a starting material. nat The use of Ni at a later point reduces the radionuclide purity of the product. Most cobalt isotopes can be separated in the purification process, but110m Ag, 108m Ag and 109 Cd 61 The nickel solution is further used to recycle the irradiated target coating. Long-lived radionuclides are problematic in terms of radiation burden to patients and accumulation of radioactive waste. Third-party coin manufacturers have not disclosed contamination from non-niobium coin backings (e.g., silver). Methods for making and using niobium-containing coins, as provided by this disclosure, represent advantages in terms of, for example, the radionuclide and chemical purity of the samples produced after subatomic particle bombardment, isolation, and purification. 61 Known effects of Cu 61 A detailed comparison of Cu products (prepared by prior art methods of plating Ag backings and targets) is provided below.

[0347] Considering these factors, niobium backing materials were selected for their inertness to acids at room and elevated temperatures. This property allows the niobium backing material to withstand the acidic media used during the dissolution and purification process. This allows for higher radionuclide and chemical purity to be achieved in the aqueous radioactive metal solution, ultimately resulting in the desired purity. 61 Higher purity of radiopharmaceuticals prepared from Cu isotopes is obtained. Although plating methods for niobium exist, this element has not yet been used in the production of radionuclides due to the poor adhesion of plated Ni materials (as discussed above). 68 For producing Ga 68The nickel (Zn) must be sufficiently adhesive to withstand the thermal load (1200 W) during irradiation and the pneumatic shuttle acceleration and sudden stop at the head at pressures of 5 to 7 bar. However, the plated nickel (or Zn) must also be sufficiently soluble during the melting and refining process. Attempts have been made to plasma-coat niobium backings to plate nickel (Ni). However, this process resulted in the loss of Ni from the niobium backing and incomplete dissolution. The thermal process 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 completely dissolve, causing its loss. The plasma coating process itself resulted in very high losses of the target coating, making the process unusable, especially with very expensive and highly enriched target metals. The main reference for this overview is the IAEA document on cyclotron radionuclide production, "IAEA RADIOISOTOPES AND RADIOPHARMACEUTICALS, REPORTS, No. 1" (INTERNATIONAL ATOMIC ENERGY AGENCY VIENNA, 2016). A monetary assessment of the procurement costs of niobium, utilized as a backing material, indicates a 40% lower cost compared to commonly used backing materials such as gold, silver, and platinum, whose costs range from 80 to 120 euros per backing material (single coin).

[0348] In parallel with this, elements related to the radiochemical purity of the labeling process are controlled by producing the plating solution under the controlled conditions described herein. By sourcing the plating solution from raw materials such as nickel, the possibility of contamination is independent of external sources and suppliers. Materials and equipment used in these cases include inert glass beakers and Falcon tubes (guaranteed to be free of undesired substances), TraceSelect purified water, pure reagents (trace metal grade), inert coin adapters and electrolytic cells (on the electroplating unit). This allows trace metal contaminants to be minimized, reduced, or avoided altogether. This difference between 99.9% purity and 99.99% purity plays a role in the resulting chemical purity of the radionuclide and, therefore, the radiochemical purity of the radiopharmaceutical prepared from the radionuclide; the presence of non-radioactive Cu, Zn, Fe, Sn, Ti, or Al, or any of their salts, can affect the purity of the desired radionuclide ( 61 This is problematic because it competes with Cu) for binding to the chelator in the tracer.

[0349] The robustness of the plating is tested by drop damage testing. This evaluation ensures that the electrodeposited substrate on the backing can withstand the mechanical shock of the shuttle system and establishes high survivability under the cyclotron beam.

[0350] In a specific embodiment, the coins are irradiated with 8.4 MeV deuterons at 40 μA to 45 μA for an average of 120 minutes, or with 13.2 MeV deuterons at 40 μA to 45 μA, using the GE shuttle system at the ARTMS or GE PET Trace cyclotron.

[0351] In a specific embodiment, coins are irradiated with 8.4 MeV deuterons at a range of 40 μA to 45 μA for an average of 120 minutes, or with 13 MeV protons at 10 μA to 100 μA, using a GE shuttle system at the ARTMS or GE PET Trace cyclotron.

[0352] Dissolution of Ni from the niobium backing is achieved by utilizing a dissolution system in 10 M HCl. 61 Cu is purified with two subsequent ion exchange resins in the FASTlab synthesis unit. The processing time for these purifications can reach up to 60 minutes.

[0353] The obtained plating material [ 61 The Cu[Cu]CuCl solution has an average radioactivity of 1.7-4.5 GBq. This radioactivity is measured for its radionuclide purity by a calibrated gamma spectrometer using dose calibrators, e.g., at PSI (Switzerland).

[0354] Gamma spectroscopy measurements were performed to identify any radionuclides, particularly long-lived radionuclides. These results demonstrate that the niobium backing material is more sensitive to the ion beam radiation than the silver backing material when utilizing the methods disclosed herein. nat Ni and 61 The results show an 89.3% and 94% reduction in Ni impurities. The non-radioactive melt product was subjected to ICP-MS analysis by Labor Veritas (Switzerland) to monitor the elemental impurities present in the product according to ICH-Q3D. All detected impurities are within the regulated ICH-Q3D concentrations (see ICH-Q3D Guidelines, pg 25).

[0355] Highly enriched 61 Ni plating is also achieved by proton irradiation (typically 10 μA to 100 μA, 13 MeV protons, 20 min to 2 h, and 61 Higher yields and industrial production using Cu (up to one half-life of Cu) are possible with the same plating parameters as above.

[0356] Following automated transport of the irradiated coin from the cyclotron to the hot cell docking station, the capsule was transferred to the QIS dissolution unit using tongs. The converted target metal was dissolved from the niobium backing material using 4 mL of 1:1 7 M HCl:30% HO (Ultrace Analysis, Merck). The acid-peroxide mixture was circulated, immersing the coin and target metal surfaces, at 2 mL / min for approximately 23 minutes at approximately 60 °C to dissolve all irradiated elements. Once the target metal was completely dissolved, the acid solution containing the dissolved metal was removed, and the QIS system was flushed with 3 mL of 10 M HCl. The combined acid solution was then fed into the FASTlab purification unit.

[0357] New 61 Cu radiotracer PSMA-I&T, SS (somatostatin) analogs, and 61 No radioactive tracers containing FAP inhibitors in combination with Cu have been reported. Therefore, NODAGA-PSMA-I&T, NODAGA-LM3, NODAGA-F1, NODAGA-F2, NODAGA-F3, and NODAGA-F4 are new precursors or intermediates, as discussed herein. Similarly, radioactive tracers [ 61 Cu]Cu-NODAGA-PSMA-I&T,[ 61 Cu]Cu-NODAGA-LM3,[ 61 Cu]Cu-NODAGA-F1,[ 61 Cu]Cu-NODAGA-F2,[ 61 Cu]Cu-NODAGA-F3,[ 61 Cu]Cu-NODAGA-F4,[ 61 Cu]Cu-NODAGA-FAPI-46 is also novel.

[0358] [ 61 Cu]Cu-NODAGA-PSMA-I&T: A novel radiotracer for PET imaging of prostate cancer Over the past few years, radiotracers targeting prostate-specific membrane antigen (PSMA) have had an impact on the imaging and management of prostate cancer. 68Ga-labeled urea-based PSMA inhibitors are the most commonly used radiotracers in this disease entity. 18 F-labeled derivatives have become an alternative to meet the increasing demand for PET imaging, primarily targeting PSMA. However, this comes at the expense of the ease of radiolabeling chelator-based kits and the potential for therapeutic companions (theranostics), which are possible alternatives with radiometals. Alternatively, in certain embodiments, 18 The attractive logistics of F, chelator-based radiochemistry, and further therapeutic options (e.g., 67 Cyclotron generation in combination with Cu 61 Cu(Eβ + Average=500keV, Eβ + max=1216keV, t 1 / 2 = 3.34 hours) is disclosed herein. 61 We report the first preclinical data on the Cu]Cu-NODAGA-PSMA-I&T radiotracer.

[0359] [ 61 Cu]CuCl2 was generated from an irradiated Ni target at the University Hospital Zurich cyclotron, followed by cassette-based automated separation as previously described (1). DOTAGA-(Iy)fk(Sub-KuE) (PSMA-I&T, here DOTAGA-PSMA-I&T) (2) and NODAGA-(Iy)fk(Sub-KuE) (NODAGA-PSMA-I&T) were prepared in ammonium acetate buffer, pH 8, at room temperature (95 °C for the DOTAGA chelator) [ 61 Labeled with Cu]CuCl2. 61 Both Cu]Cu-PSMA radiotracers were evaluated head-to-head in vitro using LNCaP cells and by dynamic and static PET / CT imaging and biodistribution studies in LNCaP xenografted nude mice.

[0360] [ 61 Cu]Cu-NODAGA-PSMA-I&T and [ 61Cu]Cu-DOTAGA-PSMA-I&T was prepared with a molar radioactivity of 24 MBq / nmol without the need for post-purification. 61 Cu]Cu-NODAGA-PSMA-I&T 61 [Cu]Cu-DOTAGA-PSMA-I&T were more hydrophilic than [Cu]Cu-DOTAGA-PSMA-I&T (log D = -2.95 ± 0.08 and -2.69 ± 0.44, respectively). In vitro, both radiotracers showed similar PSMA-mediated cellular uptake (approximately 35% after 2 hours at 37°C), with 50-60% internalization. 61 Cu]Cu-NODAGA-PSMA-I&T vs. [ 61 PET / CT images of Cu]Cu-DOTAGA-PSMA-I&T showed clear differences. 61 Cu]Cu-NODAGA-PSMA-I&T accumulated in tumors, increasing from 15 to 60 minutes p.i., and in the kidneys. Renal uptake could be reduced by adjusting the injected mass. 61 Cu]Cu-DOTAGA-PSMA-I&T 61 Cu]Cu-NODAGA-PSMA-I&T showed lower tumor uptake than [Cu]Cu-NODAGA-PSMA-I&T, but also showed lower kidney uptake and higher radioactivity in the liver. 61 This may be due to the in vivo instability of the [Cu]Cu-DOTAGA complex. We present a comprehensive biodistribution study of both radiotracers in LNCaP xenografts.

[0361] NODAGA chelating agent has the following properties compared to DOTAGA chelating agent: 61 It has been confirmed that it is a perfect match for Cu-based radioactive tracers. 61 Cu]Cu-NODAGA-PSMA-I&T 61 Cu]Cu-DOTAGA-PSMA-I&T exhibited better properties, including but not limited to, higher tumor uptake and lower background radioactivity, potentially due to its greater in vivo stability. 61 Cu]Cu-NODAGA-PSMA-I&T 61Cu]Cu-based PSMA-targeted PET imaging is a potential candidate for clinical translation.

[0362] for PET imaging of prostate cancer 61 Cu]Cu-PSMA-I&T vs. [ 68 Ga]Ga-PSMA-I&T Prostate-specific membrane antigen (PSMA) targeting is a highly relevant targeting approach for the detection and treatment (theranostics) of prostate cancer. A number of low-molecular-weight PSMA inhibitors have been developed for this purpose, [ 68 [Ga]Ga-PSMA-11 was recently approved. 68 Ga]Ga-PSMA-617 and [ 68 Others, such as [Ga]Ga-PSMA-I&T, 177 When labeled with Lu, it offers further theranostic potential. Considering the increasing clinical demand, 68 The production capacity of the Ga tracer-producing generator (2–3 patient doses) raises particular concerns. 61 Cu (Eβ + Average=500keV, Eβ + max=1216keV, t 1 / 2 =3.34 hours). 61 Cu can be produced in cyclotrons on a large scale, 68 Compared to Ga, its lower energy and longer half-life (enabling delayed imaging) can result in improved imaging quality. 61 Cu is a therapeutic companion 67 Cu. In this specification, PSMA-I&T-based [ 61 Cu]Cu-PSMA vs. [ 68 We report a comparison of Ga]Ga-PSMA.

[0363] The chelator DOTAGA on PSMA-I&T (referred to herein as DOTAGA-PSMA-I&T) was used to induce a more stable Cu-DOTAGA complex in vivo compared to Cu-DOTAGA. 61 For labeling with Cu, NODAGA was substituted.61 Cu]CuCl2 was produced from an irradiated Ni target at the University Hospital Zurich cyclotron, followed by cassette-based automated separation, as previously described (1). 61 Cu]Cu-NODAGA-PSMA-I&T was evaluated for lipophilicity, in vitro cellular uptake in LNCaP cells, PET / CT imaging, and quantitative biodistribution in LNCaP xenograft nude mice. 68 The two radiotracers were prepared with molar radioactivities of 24-30 MBq / nmol. 61 Cu]Cu-NODAGA-PSMA-I&T 68 Compared with [Ga]Ga-DOTAGA-PSMA-I&T, [Ga]Ga-DOTAGA-PSMA-I&T showed higher hydrophilicity (logD = -2.95 ± 0.08 and -2.79 ± 0.41, respectively) and higher cellular uptake in vitro (20.6 ± 2.3% cellular uptake and 9.8 ± 1.3% internalized fraction, compared with 26.6 ± 0.9% and 12 ± 1.9% internalized, respectively, after 1 h at 37°C. PET / CT imaging at 1 h pi revealed the same biodistribution pattern for both radiotracers, characterized primarily by accumulation within the tumor, with [Ga]Ga-DOTAGA-PSMA-I&T exhibiting a higher cellular uptake in vitro compared with 20.6 ± 2.3% cellular uptake and 9.8 ± 1.3% internalized fraction, compared with 26.6 ± 0.9% and 12 ± 1.9% internalized, respectively). PET / CT imaging at 1 h pi revealed the same biodistribution pattern for both radiotracers, characterized primarily by accumulation within the tumor and [Ga]Ga-DOTAGA-PSMA-I&T. 61 Cu]Cu-NODAGA-PSMA-I&T showed higher uptake and was characterized by accumulation in the kidney. 61 The biodistribution pattern of Cu]Cu-NODAGA-PSMA-I&T was similar in PET / CT images at 4 hours p.i. 61 Renal uptake of Cu-NODAGA-PSMA-I&T was significantly reduced to 96%, 72%, and 34% IA / g at 1 hour pi by increasing the injection dose to 200, 400, and 1000 pmol, respectively. 61 Cu]Cu-NODAGA-PSMA-I&T showed significant changes in whole-body distribution on PET / CT images. 68 It compares well with [Ga]Ga-DOTAGA-PSMA-I&T but shows higher tumor uptake and offers the possibility of delayed imaging. 61Cu]Cu-NODAGA-PSMA-I&T was established [ 68 [Ga]Ga-PSMA tracer is being considered for clinical evaluation. References: 1. J. Svedjehed et al., EJNMMI Radiopharmacy and Chemistry 2020;5:21.

[0364] Provided herein are methods for making target coins for use in medical cyclotrons (particle accelerators), methods for using the coins to produce high-purity radioactive copper compositions, methods for making targeted chelator constructs, and methods for using the high-purity radioactive copper compositions to prepare radiotracers. Also provided herein are methods for the use of target coins for use in medical cyclotrons (particle accelerators), methods for using the coins to produce high-purity radioactive copper compositions, methods for making targeted chelator constructs, and methods for using the high-purity radioactive copper compositions to prepare radiotracers. 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-F4 and [ 61 Extensive in vitro and in vivo characterization of the Cu]Cu-NODAGA-FAPI-46 construct is also provided, and [ 61 Cu]Cu-NODAGA-PSMA-I&T and the radioactive tracer currently in clinical use, [ 68 Ga]Ga-PSMA-I&T,[ 68 Ga]Ga-PSMA-11 and [ 18 Includes a direct comparison with [F]F-PSMA-1007. 18 For the known structure of [F]F-PSMA-1007, see Katzschmann et al. 2021 Pharmaceuticals 14(3):188. 61 Cu]Cu-NODAGA-TOC vs. [ 61 Cu]Cu-NODAGA-LM3 pair [ 68Direct comparison of Ga]Ga-DOTA-TOC (currently in clinical use) and radiotracer [Ga]Ga-DOTA-TOC in preparation for a phase I clinical trial (ongoing) 61 Cu]Cu-NODAGA-PSMA-I&T and [ 61 Process development of Cu]Cu-NODAGA-LM3 is also provided.

[0365] 5.1. Example 1 High purity Ni / Nb target coin 61 Cu]CuCl2 5.1.1. Preparation of plating solution 5.1.1.1 Preparation of buffer solutions Ammonium chloride (4.6 g, Aldrich: 326372, Trace Select) was weighed into a clean (metal-free) Falcon tube (50 mL) and a previously cleaned magnetic stir bar was added. If salt adhered to the walls of the Falcon tube, 6 mL of Trace Select water (Honeywell 95305) was added at once to wash the walls of the Falcon tube. 1 mL of 28% ammonium hydroxide (Sigma 338818) was added eight times using a 1000 μL pipette with each pipette tip. The Falcon lid was closed and the Falcon was vortexed (1–2 min) and shaken until all salt was dissolved (immersion in an ultrasonic bath for 1–2 min was a possible alternative). The Falcon tube could also be warmed (e.g., by rolling it between hands) to improve solubility. Temperature (e.g., approximately 23°C, preferably 23–25°C) was used. After the salt has completely dissolved, the pH acceptance criteria, pH range 9.28-9.62, must be verified by measuring the pH of the solution at RT, e.g., with an electronic pH meter. The Falcon tube was closed with parafilm and stored at room temperature. Any solid salt formers were redissolved before use.

[0366] 5.1.1.2 Preparation of nickel nitrate plating solution A 50 mL glass beaker was washed with nitric acid (Trace Select) followed by water (Trace Select). In a fume hood, the beaker was placed on a heating plate set at 150 °C to dry. 210 μg of natural (isotope distribution) nickel (powder, Sigma-Aldrich, <50 μm, 99.7% trace metals basis), essentially free of impurities except iron (copper impurity <0.3 ppm), was weighed into the beaker, and 4 mL of 65% nitric acid was added using a pipette. The beaker was placed back on the active heating plate, and stirring was set to 300 rpm. Ensure that the fume hood ventilation is functioning properly (NO2 evolution). During dissolution, the solution turned green. The solution was reduced to a volume of approximately 600 μL by evaporation, removed from the heating plate, and allowed to cool to room temperature. The remaining solution was transferred to a 50 mL metal-free Falcon tube. The glass beaker was rinsed with 2.8 mL of Trace Select water in 0.8 mL, 1 mL, and 1 mL steps, and each step was transferred to a Falcon tube before the next wash fraction was added. Buffer solution (4 mL), 11 mL of Trace Select water, and 3 mL of ammonium hydroxide 28% (Sigma 338818) were added to the Falcon tube. The pH of the solution was measured and adjusted to the required pH by adding ammonium hydroxide 28% (Aldrich 338818) using a sterile B-Braun syringe.

[0367] 5.1.1.3 60 Ni and 61 Examples of suitable starting materials for preparing Ni electroplating solutions Below is 60 Ni and 61 An example of a Ni lot (certificate provided by Isoflex, USA, March 2018): [Table 8] [Table 9] [Table 10]

[0368] The sample of natural nickel from Sigma-Aldrich was essentially free of any impurities except iron. Copper impurities amount to <0.3 ppm. See Certificate of Analysis in Example 2. Further suitable sources of natural Ni include: Nickel powder, <50μm, 99.7% trace metals basis Nickel rod, diameter 6.35mm, =99.99% trace metals basis Nickel foil, 0.5mm thick, 99.98% trace metals

[0369] 5.1.1.4 Preparation of zinc nitrate plating solution A 50 mL glass beaker was washed with nitric acid (Trace Select) followed by water (Trace Select). In a fume hood, the beaker was placed on a heating plate set at 150 °C to dry. 210 μg of natural (isotope-distributed) zinc (zinc powder, Sigma-Aldrich, <10 μm, >98%) was weighed into the beaker and 4 mL of 65% nitric acid was added using a pipette. The beaker was placed back on the active heating plate and the stirring was set to 300 rpm. Ensure that the fume hood ventilation is functioning properly (NO2 evolution). During dissolution, the solution turned green. The solution was reduced to a volume of approximately 600 μL by evaporation, removed from the heating plate, and allowed to cool to room temperature. The remaining solution was transferred to a 50 mL metal-free falcon tube. The glass beaker was rinsed with 2.8 mL of Trace Select water in 0.8 mL, 1 mL, and 1 mL steps, each of which was transferred to a falcon tube before the next wash fraction was added. 4 mL of buffer (prepared in Section 5.2.1.1), 11 mL of Trace Select water, and 3 mL of ammonium hydroxide 28% (Sigma 338818) were added to a Falcon tube. The pH of the solution was measured and adjusted to the required pH by adding ammonium hydroxide 28% (Aldrich 338818) using a sterile B-Braun syringe.

[0370] 5.1.2. Electroplating of the backing surface A niobium backing disk (28 mm x 1.0 mm) was obtained from the high-purity Nb described herein. It was washed with ethanol (high purity) and inserted into a Comecer V21204 electroplating unit. A platinum wire anode was positioned approximately 1-3 mm from the coin surface, adjusted using a polymer spacer. The coin mass was determined to be 5.25 grams. The niobium backing (22 mm x 1.0 mm, weighing 3.3 g) was used. The plating solution was poured into the electrolyte container and attached to the device. The voltage was set to 4.5 V. After 5 minutes of stabilization, the measured current was 180 μA. The pump duty cycle was set to 45%. The plating solution changed from blue to transparent, and a gradual current decrease to 160 μA was observed over 120 minutes. The plating process was stopped. The coin was removed from the electrolytic cell and weighed. Microscopic evaluation of the coin was also performed using a DINOLite digital microscope (Figures 1 and 2) to observe the surface crystalline structure and uniformity. The coins (Figure 2) were stored in metal-free Falcon tubes under a nitrogen atmosphere.

[0371] 5.1.3.Electroplating Results After electroplating was completed, microscopic evaluation of the coins was performed using a DINOLite digital microscope to observe the crystalline structure and uniformity of the surface. As can be seen in Figure 1 (panels A-C), a homogeneous target coating with durable adhesion was obtained (see also Figure 2).

[0372] 5.1.4. High purity [ 61 General guidelines for the production of Cu]Cl2 The purpose of this example is to identify natural nickel and / or enriched nickel. 60 Deuteron irradiation of Ni to copper-61( 61 The goal of this work was to enable mass production of ZnO (Cu). This work was a proof of concept and therefore 61 There was no benchmark specification for Cu. However, the inventors 60 After Ni irradiation, 61 Cu] to generate CuCl2, or natOptimize target performance, target geometry / material use, irradiation parameters, and chemical processing methods to scale for Ni irradiation. While no explicit pharmacopoeial specifications exist for radioactive copper, testing QC methods include evaluation of radionuclide purity and molar activity (extracted [ 61 Cu] to demonstrate the usefulness of CuCl2).

[0373] In this example, two different types of targets, natural nickel ( nat Ni) target and highly enriched nickel-60 ( 60 Ni) targets, both of which were suitable for deuteron bombardment. However, nat Ni was available at low cost and in high purity, 60 Ni remains expensive and requires efficient means. If even higher yields are desired, target preparation efforts should focus on proton-based 61 Ni(p,n) 61 Although it can be directly converted to Cu pathway, enrichment 61 Considering the cost of Ni (approximately US$25 / μg), such an approach imposes the need for targeted recycling.

[0374] The following set of guidelines is for the production of high purity [Nb from Nb coins having Zn or Ni (optionally isotopically enriched) coatings electroplated thereon as provided herein. 61 Cu]CuCl2, 61 This protocol allows for the production of Cu targets of all types. Specific details are provided for deuteron and proton irradiation, respectively. This protocol was followed and evaluated in the following examples. 61 All Cu compositions were produced. [Table 11-1] [Table 11-2] [Table 11-3] [Table 11-4] [Table 11-5]

[0375] 5.1.5.[ 61 Purification and Characterization of Cu]CuCl2 and Waste Streams The solid target irradiation material was dissolved in a total volume of 7 mL of 6 M HCl with the addition of 30% hydrogen peroxide via a dissolution chamber.

[0376] Separation and purification were achieved using a cassette-based FASTlab platform using TBP (tributyl phosphate-based) resin (1 mL) (particle size 50-100 μm; pre-packed, Triske) and then weakly basic (tertiary amine; TK201) resin (2 mL) (particle size 50-100 μm; pre-packed, Triske) pre-conditioned with HO (7 mL) and HCl (10 M, 7 mL), respectively. Cassette reagent vials were prepared using concentrated HCl (Optima grade, Fisher Scientific), NaCl (ACS, Fisher Scientific), and Milli-Q water (Millipore system, 18 MΩ cm resistivity). 6 M HCl (2 × 4.2 mL), 0.05 M HCl with 5 M NaCl (4.2 mL), and then subsequent 61 Cu was purified on two subsequent ion exchange resins in the FASTlab synthesis unit.

[0377] 1) The acid-adjusted dissolution solution (approximately 7 mL) was loaded onto both columns in series and directed to the "Ni collection fraction." The TBP resin retained the Fe 3+ It acts as a guard column by quantitatively retaining ions, and Cu 2+ and Co 2+ The complex was quantitatively retained on a tertiary amine (TK201) resin.

[0378] 2) To maximize Ni recovery for future recycle, both columns were washed with 6 M HCl (4 mL).

[0379] 3) The TK201 column was washed with 4.5 M HCl (5.5 mL) to elute most of the cobalt salts.

[0380] 4) The TK201 column was washed with 5M NaCl in 0.05M HCl (4 mL) to reduce residual acid on the resin and further remove residual cobalt salts.

[0381] 5) Wash the TK201 column with 0.05 M HCl (3 mL) and 61 Cu]CuCl2 was quantitatively eluted.

[0382] The obtained plating material [ 61 The Cu[Cu]CuCl solutions have an average radioactivity of 1.0–4.5 GBq, which was measured by a PSI (Switzerland) gamma spectrometer using Comecer dose calibrators and their radionuclide purity.

[0383] Gamma spectroscopy measurements were performed to identify any radionuclides, particularly long-lived radionuclides. These results demonstrate that the niobium backing material is more sensitive to the ion beam radiation than the silver backing material when utilizing the methods disclosed herein. nat Ni and 61 The results show an 89.3% and 94% reduction in Ni impurities. ICP-MS measurements were performed by Labor Veritas (Switzerland) on the non-radioactive melt product to monitor the elemental impurities present in the product according to ICH-Q3D. All detected impurities were within the regulated ICH-Q3D concentrations (see ICH-Q3D Guidelines, pg 25).

[0384] Highly enriched 61 Ni plating is also achieved by proton irradiation (typically 80 μA to 100 μA, 13 MeV protons, 1 to 2 hours, and 61Higher yields and industrial production using Cu (up to one half-life of Cu) were possible with the same plating parameters as above. 5.1.6.Using Nb backing coins nat Ni(d,n) 61 Cu and 60 Ni(d,n) 61 Prepared from Cu 61 Purity and radioactivity assessment of Cu]CuCl2 compositions.

[0385] This example was produced using the Nb backing, Ni electrodeposited coin of the present disclosure. 61 Radioactivity of Cu, and natural nickel targets, including coins and targets enriched 60 Coins containing Ni, i.e., nat Ni(d,n) 61 Cu and 60 Ni(d,n) 61 Cu is used to present information on cobalt radioisotopes produced by deuteron irradiation. The irradiated material was dissolved and purified as described in Example 3.

[0386] Natural Nickel / Nb coins and 60 Obtained and purified during purification from the products of deuteron irradiation of Ni / Nb coins 61 The Cu products and waste were treated and analyzed by gamma spectroscopy and are shown below. Natural Nickel / Nb coins and enriched 60 Thick target yield calculations based on TENDL-2019 using isotopic abundances of Ni / Nb coins.

[0387] 5.1.7. Radioactive Cobalt Content Table 8 shows nat The radioactivity of the cobalt radioisotope in the different fractions after FASTlab purification is included as an average of three measurements (n = 3 irradiations) using a Ni / Nb target coin. The radioactivity was extrapolated to 3 hours, 50 μA beam, EoB (end of bombardment) + 2 hours. 61The radioactivity of Cu]CuCl2 was experimentally determined and found to be approximately 80% of the estimate based on TENDL-2019.

[0388] Generated for deuteron irradiation at 8.4 MeV, 50 μA for 3 hours, 80% efficiency (EoB+2 hours) 61 Radioactivity of Cu: 3052MBq. Time course of cobalt radioisotopes and 61 See also Figure 3 for the corresponding change in Cu purity. [Table 12]

[0389] Table 9 shows the target metals enriched to 99% 60 The calculated activity of the cobalt radioisotope obtained by using Ni is included. The activity was extrapolated to a 3-hour, 50 μA beam, EoB (end of bombardment) + 2 hours. 61 The radioactivity of Cu was calculated.

[0390] Generated by deuteron irradiation at 8.4 MeV, 50 μA for 3 hours with 80% efficiency (EoB+2 hours) 61 Radioactivity of Cu: 11.552MBq. Time course of cobalt radioisotopes and 61 See also Figure 4 for the corresponding change in Cu purity. [Table 13]

[0391] 5.1.7.1 Radioactivity and Chemical Purity The process described herein was used based on the radioactivity (MBq) measured at different beam currents (µA) and timescales (5-60 min). nat Ni, 60 Deuteron bombardment of Ni and 61 The measured radioactivity resulting from proton bombardment of Ni was found to be approximately >80% of the theoretical radioactivity calculated using the TENDL-19 cross-section database.

[0392] The radioactivity of radiocobalt and other long-lived radionuclides was measured after release (more than 3 weeks after bombardment), and then the EOB activity of long-lived impurities was extrapolated.

[0393] Table 10 shows the results of the target metals for 50 μA, 3 hours of deuteron irradiation after FASTlab purification. nat Generated by Ni 61 Cu] CuCl2 solution and the extrapolated radioactive cobalt content 61 Indicates Cu purity. [Table 14]

[0394] Assuming a product expiration time, e.g., more than 3 weeks after EoB, less than 0.03% of non-Cu radioisotopes ( 56 Co and 58 Co) remains in the copper fraction. This value is lower than the permissible limit for Ga-68 cyclotron production as found in the Pharmacopoeia (0.1% at expiry for non-Ga radioisotopes):

[0395] nat Derived from Ni irradiation 64 Cu (approximately 5% content at expiration) is the main impurity, and it is found to be more resistant to longer exposure times or shelf life. 61 Cu reduces the radioisotopic purity of the product (shown as the gray curve in Figure 3).

[0396] Table 11: 60 Ni / Nb target coin- 61 After analysis of Cu radioactivity and purity and FASTlab purification, Figure 4 shows the prepared [ 61 Cu] CuCl2 solution and the extrapolated radioactive cobalt content 61 Indicates Cu purity. [Table 15]

[0397] Assuming a product expiration time of 8 hours after EoB, less than 0.01% of non-Cu radioisotopes ( 56 Co and 58 Co) remained in the Cu fraction. This value is found in the Pharmacopoeia 68 This was 10 times lower than the limit allowed for Ga cyclotron production (0.1%* at expiration for non-Ga radioisotopes).

[0398] Copper fraction less than 0.02% at 8 hours expiration time after EoB 64 Cu remains, 68 This was 100 times lower than the specifications required for Ga ( 68 2% Ga radioisotope was allowed for Ga). 5.1.8.Ni / Nb target coins produced from 61 Purity of Cu]CuCl2: Comparison with commercially available radionuclides

[0399] Table 12 compares regulatory specifications for purity of commercially available radionuclides for natNi / Nb and enriched 60 High purity [ 61 Cu]CuCl2 and after FASTlab purification. [Table 16]

[0400] The first notable comparison is the 68 Cyclotron production of Ga also produces long-lived radionuclides (see, for example, Applied Radiation and Isotopes 65(10), 1101-1107, IAEA-TECDOC-1863 Gallium-68 Cyclotron Production), especially 66 Zn(p,pn) 65 from Zn decay 65 Zn (half-life = 244 days) is produced. 68 Approximately 0.365% of the Zn starting target metal 66 Zn, about 770 Bq65 Zn is produced from a 50 μA, 3-hour beam with an energy of 13 MeV in a thick target (TENDL-2019 based calculations). 66 Using natural Zn with an abundance of 27.7% in Zn, 58 kBq 65 Zn is produced in a single 3-hour beam run at 50 μA. Therefore, the isotopic purity of Zn in the target metal is very important.

[0401] [ 61 Similar to the formation of Cu]CuCl2, [ 64 Cyclotron production of Cu]CuCl2 also involves long-lived cobalt radionuclides, i.e. 55 Co, 57 Co, 58 Co and 60 Co is produced (see, for example, Nuclear Medicine & Biology, Vol. 24, pp. 35-43, 1997, "Applied Radiation and Isotopes" 68 (2010) 5-13). By operating with a depleted beam of less than 13 MeV, ( 64 Ni(p,na) 60 (from Co) 60 Co was reduced to 1 Bq per 50 μA, 3-hour run. For beam energies below 13 MeV, 58 Ni(p,a) 55 Co formed from the reaction 55 Co remains the main impurity (half-life = 17.53 hours). 57 The 170 Bq of Co was about 170 Bq under these conditions, mainly 60 Ni(p,a) 57 It was formed from Co.

[0402] Note: These estimates are based on the TENDL-2019 cross-sectional data and enrichment data, as follows: 64 Calculated from thick target yield using Ni isotopic abundance: 0.00376% 58 Ni, 0.00298% 60 Ni, 0.0058% 61Ni, 0.135% 62 Ni, 99.858% 64 Ni.

[0403] Example 1B. Nb enrichment as a target metal on backcoins 61 Ni 61 Cu is high purity 61 Via a cyclotron equipped with a solid target system that irradiates high-purity niobium coins plated with Ni (purity 99.42%), 61 This was produced by proton bombardment of Nb backcoins electroplated with Ni. The proton beam current used was up to 100 μA, and the beam energy was 13 MeV. An aluminum beam degrader was used.

[0404] The solid target irradiation material was dissolved in a total volume of 7 mL of 6 M HCl with the addition of 30% H2O2 in a heated dissolution chamber. 61 Cu was purified from metal and radiometal impurities via a GE Healthcare FASTlab 2 module through a tributyl phosphate resin cartridge and a tertiary amine-based weak ion exchange resin containing a long-chain alcohol. Finally, the product was eluted in 3 mL of 0.05 M HCl in an ISO Class 5 environment through a Millex 4 mm Durapore PVDF 0.22 μm sterile filter into a sterile evacuated vial. The vials can be handled carefully using appropriate shielding for transport and handling and can be stored at room temperature until use. [Table 17]

[0405] As shown in Table 14 and Figure 5, commercially available [ 61 Cu]CuCl2 is 110m Ag and 109 In addition to Cd, radionuclide impurities, especially at high levels 56 Co and 58Co. Removal of Ag and Cd isotopes from Cu-61 products by replacing silver with niobium as the backing material. 56 There was a 9-fold reduction in Co isotopes and a greater than 2000-fold reduction in Ni-61 (requiring less shielding of the radioactive waste). A 50% reduction in long-lived cobalt isotopes (early final disposal of the waste produced) was also observed. The following data demonstrate that the [ 61 It was clear that the radionuclide purity of [Cu]CuCl2 was shown to be superior to previously known methods and products. High levels of long-lived Co, Ag, and Cd radionuclides contribute to the radiation burden in patients, as well as to the radiopharmaceutical manufacturing and radiolabeling processes. 61 This creates a radioactive waste problem for consumables that come into contact with the Cu]CuCl2 product. [Table 18]

[0406] All radionuclide impurity profiles were combined and are shown in Table 15 below and Figure 6, demonstrating an 83% reduction in radionuclide impurities. 61 If present in the [Cu]CuCl2 product, they may cause radiation burden to the patient, waste problems, and reduce the quality of the radiopharmaceutical. 61 It may interfere with the chelation process by competing with Cu, which affects the accurate radiolabeling of the tracer. When the backing material was changed from silver to the niobium backing provided herein and the Ni plating method described herein was used, an 89.3% reduction in impurities was observed.

[0407] When Ni-61 was used as the starting material, a further reduction of 46% was observed. [Table 19]

[0408] At EoB and EoS (EoB+2) 61 As a result of the purity of Cu, long-lived radionuclide impurities decay more slowly and therefore on longer timescales. 61 The concentration increases with respect to Cu. Therefore, the impurity profile can vary greatly based on the isotopic enrichment, purity, method, and process of producing the coins. 61 Cu]CuCl2 product, affecting the type and amount of radionuclide impurities.

[0409] FIG. 7 shows the results of irradiation of Ni target metal electrodeposited according to the present disclosure onto a high purity Nb backing, as assessed by gamma spectroscopy at t=0 and t=12 hours (Bq / g, total radionuclide impurities) [ 61 Compared to the radionuclide purity of the [Cu]CuCl2 solution produced using a commercially available natNi target metal on an Ag backing, 61 [Cu]CuCl2 solutions as produced by irradiation of Ni target coatings electroplated according to the present disclosure onto high purity Nb backings. 61 This highlights the excellent quality of the [Cu]CuCl2 solution, with its purity after 12 hours still far exceeding the purity limits set by the Pharmacopoeia for similar radionuclides for medical use. [Table 20]

[0410] 5.1.9. Endotoxin measurement using horseshoe crab hemocyte lysate (LAL test) Bacterial endotoxin was determined by LAL testing using the Charles River Endosafe™-PTS system.

[0411] [ 61 During dispensing of the [Cu]CuCl2 solution, 1 mL aliquots were dispensed for quality control testing. Testing was performed in an unclassified quality control laboratory. The solution was 61Cu]CuCl2, 0.05 M HCl (aq). [Table 21]

[0412] Before analysis, 61 The CuCl solution (pH 1.3) was diluted with LAL reagent water and buffer to reach a pH value in the range of 6 to 7.6. To adjust the pH, TRIS buffer was added. 61 Cu]CuCl2 solution.

[0413] The test subject 61 Dilutions of Cu]CuCl2 were prepared and the reagents in endotoxin-free dilution tubes were mixed as follows: dilution factor (1:75); 61 Cu]CuCl sample (10 μL); TRIS buffer (40 μL); water (700 μL). Mix for approximately 30 seconds.

[0414] 5.1.10. Conclusion Generated after deuteron irradiation 61 The experimental activity of Cu is approximately 80% of the theoretical yield calculated from the TENDL-2019 cross-sectional data.

[0415] 61 The main long-lived nuclides in the radioactive waste fraction from the cyclotron production of Cu are 56 Co, 57 Co, 58 Co and 60 Co is a radioactive cobalt species. 56 Co, 57 Co and 58 Co was calculated to have decayed below the regulatory clearance limit (LL*), 60 leaving only Co. *Clearance limit (LL) means the value corresponding to the activity concentration level in a material above which the handling of this material is no longer subject to mandatory authorization or supervision.

[0416] [ 61Cu]CuCl2 enriched to 99% to improve product yield and purity. 60 Ni or 61 You can use target coins with Ni. These targets allow you to 61 The extrapolated purity of the CuCl product is 64 It is higher because Cu is not formed as a radioisotopic impurity. 56 Co and 60 The Co content is reduced by 100 times. 57 The amount of Co is four times higher (but the radioactivity is lower), 58 The amount of Co doubles (but 56 Co / 58 decays below LL before Co). Example 2A - Preparation of NODAGA-PSMA-I&T

[0417] Typical 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) trifluoroacetic acid (TFA) in HO (solvent A) and 0.1% TFA (v / v) in acetonitrile (solvent B) (specific gradients are cited in the text). UV detection was performed at 220 nm using a 206 PHD UV-Vis detector (Linear™ Instruments Corporation, Reno, USA). Both retention time tR and capacity factor K' are reported 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. Synthesis of the carboxyl-protected Lys-urea-Glu core (KuE) [ka]

[0418] Step a. (S)-Di-tert-butyl 2-(1H-imidazole-1-carboxamide)pentanedioate (1) is synthesized from the di-tert-butyl ester of glutamic acid. This is reacted with carbonyldiimidazole (CDI) in the presence of triethylamine (TEA) under anhydrous conditions to form the intermediate acylimidazole derivative. HPLC (10% to 90% B in 15 min): tR = 12.2 min; K' = 5.78. Calculated monoisotopic mass for 1 (C 17 H 27 N3O5):353.4;found:m / z=376.0 [M+Na]+. [ka]

[0419] Step b. Cbz-(OtBu)KuE(OtBu)2(2): A solution of 3.40 g (9.64 mmol, 1.0 equiv.) of 1 in 45 mL of 1,2-dichloroethane (DCE) is cooled to 0 °C, and 2.69 mL (19.28 mmol, 2.0 equiv.) of triethylamine (TEA) and 3.59 g (9.64 mmol, 1.0 equiv.) of Cbz-Lys-OtBu HCl are added with vigorous stirring. The reaction mixture is heated to 40 °C overnight. The solvent is removed in vacuo, and the crude product is purified by silica gel flash chromatography using an eluent mixture of ethyl acetate / hexane / TEA (500 / 500 / 0.8 (v / v / v)). Evaporation of the solvent afforded 4.80 g of 2 as a colorless viscous oil (yield: 80% based on L-di-tert-butyl glutamate HCl). HPLC (40% to 100% B in 15 min): tR = 14.3 min; K' = 8.53. Calculated monoisotopic mass for 2 (C 32 H 51N3O9):621.8;found:m / z=622.2 [M+H]+,644.3 [M+Na]+. [ka]

[0420] Step c. (OtBu)KuE(OtBu)2(3): For Cbz deprotection, dissolve 6.037 g (9.71 mmol, 1.0 equiv.) of 2 in 150 mL of ethanol (EtOH) and add 0.6 g (1.0 mmol, 0.1 equiv.) of palladium on activated carbon (10%). After purging the flask with H2, stir the solution overnight under light H2 pressure (balloon). Filter the crude product through Celite and evaporate the solvent in vacuo to obtain the desired product as a waxy solid (4.33 g, 91.5% yield). HPLC (10% to 90% B in 15 min): tR = 12.6 min; K' = 6.41. Calculated monoisotopic mass for 3 (C 24 H 45 N3O7):487.6;found:m / z=488.3 [M+H]+,510.3 [M+Na]+. Synthesis of protected Sub-KuE conjugates [ka]

[0421] NHS-Sub-(OtBu)KuE(OtBu)2(4):3 (40 μg, 0.08 mmol, 1 equiv.) was dissolved in 500 μL of N,N-dimethylformamide (DMF) and 57 μL (0.41 mmol, 5 equiv.) of TEA was added. This solution was added dropwise (within 30 min) to a solution of 33.2 μg (0.09 mmol, 1.1 equiv.) of disuccinimidyl suberate (DSS). After stirring for another 2 h at room temperature (RT), the reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and extracted with water (twice). The organic phase was dried over Na2SO4, filtered, and evaporated to dryness. The crude product 4 was sufficiently pure to be used in the next reaction step without further purification. HPLC (10% to 90% B in 15 min): tR = 16.9 min; K' = 8.39. Calculated monoisotopic mass for 4 (C 36 H 60 N4O 12 ):740.4;found:m / z=741.2 [M+H]+,763.4 [M+Na]+. Synthesis of peptide linkers [ka]

[0422] Fmoc-3-iodo-D-Tyr-D-Phe-D-Lys(Boc) (Fmoc-(Iy)fk): Fmoc-Lys(Boc)-OH (1.5 equivalents) was dissolved in dry dichloromethane (DCM) and N,N-diisopropylethylamine (DIPEA) (1.25 equivalents) was added. The dried TCP resin was suspended and stirred at RT for 5 minutes. Another 2.5 equivalents of DIPEA was added and stirring was continued for 90 minutes. 1 mL of methanol (MeOH) was then added per gram of resin to cap any unreacted trityl chloride groups. After 15 minutes, the resin was filtered off, washed twice each with DCM, DMF, and MeOH, and dried in vacuo. The final loading of resin-bound Fmoc-Lys(Boc)-OH was calculated from the weight difference.

[0423] Assembly of the peptide sequence H2N-3-iodo-d-Tyr-d-Phe- onto the resin-bound Lys(Boc) is carried out according to standard Fmoc protocols using 1.5 equivalents of 1-hydroxybenzotriazole (HOBt) and O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) as coupling reagents, and 4.5 equivalents of DIPEA. After coupling of the last amino acid, the resin is washed, dried, and stored in a desiccator until further functionalization. Coupling of chelating moieties [ka]

[0424] Fmoc-3-iodo-D-Tyr-D-Phe-D-Lys(Boc)-TCP resin was pre-swollen in N-methyl-pyrrolidone (NMP) for 30 min. After cleavage of the N-terminal Fmoc protecting group using 20% ​​piperidine in DMF (v / v), the resin was washed eight times with NMP.

[0425] NODAGA-Iodo-D-Tyr-D-Phe-D-Lys (NODAGA-(Iy)fk, 5): For 38 μmol of resin-bound peptide, add 31 μg of NODAGA-tris-tBu-ester (57 μmol, 1.5 equiv.) in NMP, 108 μg of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU; 0.28 μmol, 5 equiv.), and 87 μL of DIPEA (570 μmol, 15 equiv.) to the resin. After shaking for 72 h, wash the resin with NMP and DCM. HPLC (10% to 90% B in 15 min): tR = 8.2 min; K' = 4.13. Calculated monoisotopic mass for 5 (C 39 H 54 IN7O 12 ):939.29;

[0426] Cleavage from the resin (2 × 30 min) and concomitant tBu deprotection are carried out using a mixture of 95% TFA, 2.5% triisobutylsilane (TIBS), and 2.5% water (v / v / v). The combined product solution is then concentrated, and the crude peptide is precipitated with diethyl ether and dried in vacuo. Due to the sufficient purity of the crude product, it is used in the next reaction step without further purification. Condensation of chelator-conjugated peptides and PSMA-binding motifs [ka]

[0427] NODAGA-(Iy)fk(Sub-KuE) (6): To a solution of 5 (15 μg, 18 μmol, 1 equiv.) and TEA (13 μL, 90 μmol, 5 equiv.) dissolved in 600 μL of DMF, 13 μg of 4 (18 μmol, 1 equiv.) dissolved in 400 μL of DMF was slowly added. After stirring at RT for 2 h, the reaction mixture was evaporated to dryness. Subsequent removal of the tBu protecting group was achieved by dissolving the crude product in TFA and stirring for 40 min. After precipitation in diethyl ether, the crude product was dissolved in water and purified using preparative RP-HPLC (25% to 40% B in 20 min). HPLC (10% to 90% B in 15 min): tR = 10.3 min; K' = 5.44. Calculated monoisotopic mass for 10 (C 59 H 85 IN 10 O 21 ):1396.5. 1 See Figures 32A-C for the H-NMR spectrum and associated chemical shifts.

[0428] Alternatively, HPLC analysis was performed on a Waters XBridge Peptide BEH C18, 250 x 4.6 mm, 3.5 μm column; eluent A: water (0.1% H3PO4); eluent B: acetonitrile (0.1% H3PO4); linear from 10% B to 90% over 15 min at 1 mL / min; detection at 215 nm; retention time 12.4 min. MALDI-TOF calc. [MH]+ 1397.5 m / z. Found 1397.8 m / z. Here, the analysis was performed in linear positive mode using cyanohydroxycinnamic acid as the matrix.

[0429] Example 2 - Native copper (Cu) targeting of PSMA ligands, somatostatin analogues and FAP ligands to NODAGA, DOTAGA and DOTA targeted chelator constructs nat Cu) complexation nat Preparation of Cu complexes was performed by dissolving each targeted chelator construct in 1.5-fold excess of ammonium acetate buffer, 0.5 M, pH 8. nat Complexation was performed by incubation with CuCl2x 2H2O at 95°C for 15 minutes (for NODAGA-constructs, 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- and DOTA-constructs, DOTAGA-PSMA-I&T, and DOTA-TOC). 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 shows the retention time (tR) and the ion [M+2H] relative to the theoretical mass. 2+ The resulting mass (mass-to-charge ratio, m / z) of the formed nat The identity of the Cu-complexed conjugate was confirmed. Table 13. natAnalytical data for Cu constructs. Analysis was performed on a Shimadzu LC2020 LC-MS system using a Waters X Bridge C18 5 μm, 150 × 4.6 mm column and a gradient of 15–65% acetonitrile (0.1% TFA) / water (0.1% TFA) for 15 min at a flow rate of 2 mL / min. For F1, F2, F3, and F4, analysis was performed on a Shimadzu LC2020 LC-MS system using a Gemini C6 Phenyl 5 μm, 250 × 4.6 mm column and a gradient of 15–80% acetonitrile (0.1% TFA) / water (0.1% TFA) for 15 min at a flow rate of 2 mL / min. [Table 22]

[0430] Example 3 - NODAGA-, DOTAGA- and DOTA-Radiotracers of PSMA Ligands and Somatostatin Analogues and FAPI Inhibitors 61 Cu label Aliquots of NODAGA-, DOTAGA-, or DOTA-targeted chelator constructs (3–6 nmol, 1 μg / mL in water) were diluted with 0.25–0.30 mL of ammonium (or sodium) acetate (0.5 M pH 8), followed by 0.1–0.7 mL of [ 61 Cu[Cu]CuCl2 was added (70–240 MBq). The reaction mixture was incubated for 15 min at different temperatures depending on the chelator. NODAGA constructs (NODAGA-PSMA-I&T, NODAGA-TOC, NODAGA-LM3, NODAGA-F1, NODAGA-F2, NODAGA-F3, NODAGA-F4, and NODAGA-FAPI-46) were incubated at room temperature (approximately 20–25 °C), while DOTAGA and DOTA constructs (DOTAGA-PSMA-I&T and DOTA-TOC) were incubated at 95 °C. The pH of the reaction mixture was 5–6.

[0431] [ 61 Preparation and testing methods for Cu]Cu-NODAGA PSMA-I&T [61 During dispensing of the [Cu]Cu-NODAGA PSMA-I&T solution, a 1 mL aliquot was dispensed for quality control testing. Testing is performed in an unclassified quality control laboratory.

[0432] The solution is 61 Cu]Cu-NODAGA PSMA-I&T, composed of 0.05 M HCl, 0.5 M sodium acetate 20 μg / mL with ascorbic acid, and 0.9% NaCl sterile solution for injection.

[0433] [ 61 The specifications for the Cu]Cu-NODAGA PSMA-I&T solution, as well as the test methods, are listed in Table 14 (quality parameters tested before release (or distribution) of the physical product) and Table 15 (quality parameters tested after release). [Table 23] [Table 24] Scheme 1. NODAGA-PSMA-I&T, NODAGA-TOC, NODAGA-LM3, NODAGA-F1, NODAGA-F3, NODAGA-F2, and NODAGA-F4 61 Cu labeling reaction. [Table 25-1] [Table 25-2]

[0434] Quality control was performed by reversed-phase high performance liquid chromatography (RP-HPLC) coupled to a radiodetector (radio-HPLC). The results of the radio-HPLC are shown in Table 16 below.

[0435] [ 61 Cu]Cu-DOTAGA-PSMA-I&T and [ 61Cu]Cu-NODAGA-PSMA-I&T was prepared at a molar radioactivity of 24 MBq / nmol without the need for post-labeling purification. [Table 26]

[0436] All constructs were synthesized in very high yields and purity. 61 Labeled with Cu. Uncomplexed 61 No further purification steps were required to remove Cu from the reaction mixture, allowing direct use of the formed radiotracer.

[0437] Example 4 - PSMA Ligands, Somatostatin Analogues and FAPI Ligands 61 Lipophilicity of Cu-labeled NODAGA-, DOTAGA-, and DOTA-radiolatracers and their 68 Comparison with Ga counterparts and reference radiotracers The lipophilicity / hydrophilicity of the radiotracer was assessed by determining the partition coefficient (D) between the aqueous and organic phases according to the "shake flask" method and expressed as log D (pH = 7.4). The radiotracer (1 μM) was added to a 50:50 presaturated mixture of 1-octanol and phosphate-buffered saline (PBS pH 7.4). The solution was vortexed for 30 minutes and then centrifuged at 3,000 rpm to achieve phase separation. Aliquots were collected from each phase and measured in a gamma counter. The partition coefficient was calculated as the logarithmic mean of the ratio of radioactivity in the organic and PBS phases. The results are summarized in Table 17. Table 17. 68 Ga radiotracer (reference radiotracer) 61 Lipophilicity expressed as the logarithmic distribution coefficient D (octanol / PBS pH 7.4) of the Cu radiotracer. Results are the mean ± standard deviation from a minimum of two separate experiments, each in triplicate. [Table 27]

[0438] [61 Cu]Cu-NODAGA-PSMA-I&T and [ 61 The lipophilicity of both Cu]Cu-DOTAGA-PSMA-I&T is comparable. 61 Cu-labeled PSMA radiotracer 68 Ga]Ga-PSMA-11, and is an approved PET tracer for PSMA imaging (Hennrich U and Eder M Pharmaceuticals 2021;14:713)[ 18 It is more lipophilic than [F]F-PSMA-1007. 68 The higher lipophilicity of [Ga]Ga-PSMA-11 has been reported to be beneficial for PSMA-based radiotracers (Wirtz M et al., EJNMMI Research 2018). 61 Cu complexation did not significantly affect the lipophilic / hydrophilic properties of the radiotracers, and their 68 It was comparable to its Ga counterpart. 61 Cu]Cu-NODAGA-TOC and [ 61 The lipophilicity of Cu-DOTA-TOC is comparable to that of the clinically used [ 68 It is more lipophilic than Ga]Ga-DOTA-TOC, and among them, 61 Cu]Cu-NODAGA-LM3 is the most lipophilic. 61 The lipophilicity of the Cu-labeled FAPI constructs is approximately the same as each other.

[0439] Example 5 - PSMA Ligands and Somatostatin Analogues nat Binding affinities of Cu-complexed NODAGA-, DOTAGA-, and DOTA-constructs and comparison with reference compounds Affinity is IC 50 This was measured by determining the concentration of the test construct that causes 50% inhibition of specific binding of a reference radioligand to the same molecular target.

[0440] For the PSMA construct, radioiodinated ((S)-1-carboxy-5-(4-(- 125I-iodo-benzamido)pentyl)carbamoyl)-L-glutamic acid ([ 125 The assay was performed on LNCaP cells (1.5 × 10 cells / well) seeded in 24-well plates. The cells were treated with 0.2 nM [I-BA]KuE. 125 In the presence of [I-BA]KuE, high concentrations of each nat After incubation with Cu-complexed conjugates (ranging from 0.1 to 100 nM) on ice for 1 hour, unbound (free) [ 125 [I-BA]KuE was harvested by removing the medium, and cells were stripped with 1 M NaOH for counting (bound radioligand). Nonspecific binding was defined as the amount of bound radioactivity in the presence of a high excess (10 μM) of the blocking agent 2-(phosphonomethyl)pentanedioic acid (2-PMPA).

[0441] For somatostatin constructs, 125 I-labeled Tyr-somatostatin-14( 125 The assay was performed with HEK cell membranes expressing human SST2 (HEK-SST2) cell membrane suspensions on 96-well plates. The membranes were incubated with 0.05 nM of 1000 ribosomal RNA (1000 ribosomal RNA). 125 In the presence of I-SS-14, each nat The cells were incubated with increasing concentrations of Cu construct (ranging from 0.001 to 100 nM). After 1 hour of incubation at 37°C, they were filtered using a Brandel 48-well Cell Harvester. The filters containing the membranes (bound radioligand) were collected for measurement. Nonspecific binding was defined as the amount of bound radioactivity in the presence of a 1,000-fold excess of SS-14.

[0442] Quantification of free and bound radioligand was performed using a gamma counter. Data were analyzed using GraphPad Prism 9 software, and IC 50 Values ​​were determined using the formula "log(inhibitor) vs. response" based on specific binding = total - nonspecific binding. IC 50 Values ​​are expressed in nM and are reported in Table 18. Table 18.IC50 The values ​​were determined by a competition assay. The PSMA constructs were reacted with the radioligand [ 125 I-BA]KuE in LNCaP cells after 1 hour of incubation on ice, and somatostatin constructs were assayed using the radioligand [ 125 I]-Tyr-somatostatin-14 was assessed in HEK-SST2 membranes after 1 h of incubation at 37° C. Results are presented as the mean ± standard deviation (SD) from at least two separate experiments, each in triplicate. [Table 28]

[0443] Two nat Cu-complexed PSMA construct and two nat The exchange of chelators from DOTAGA (reference constructs used in the clinic: DOTAGA-PSMA-I&T) and DOTA (reference constructs used in the clinic: DOTA-TOC) to the chelator NODAGA (NODAGA-PSMA-I&T and NODAGA-TOC, respectively) between Cu-complexed TOC somatostatin analogs against their molecular targets (PSMA and SST2, respectively) was shown to be beneficial. nat This indicates that the affinity of the Cu-complexed construct is not hindered. nat IC of Cu-complexed NODAGA constructs 50 The values ​​are in a similar low nanomolar range and are consistent with the corresponding DOTAGA and DOTA constructs and reference molecules, respectively. nat Ga-PSMA-11 (for PSMA I&T constructs) and nat Similar to Ga-DOTA-TOC and the natural hormone, somatostatin-14 (in the case of TOC and LM3 constructs), it shows very high affinity.

[0444] NODAGA-LM3 and nat Cu-NODAGA-LM3 IC 50 As suggested by the unchanged value of 61Radiolabeling with Cu) does not interfere with the affinity of the NODAGA-LM3 construct for its molecular target (SST2). Example 6- 61 In vitro cellular uptake of Cu radiotracer

[0445] Cellular uptake was tested in vitro using intact cells seeded overnight in 6-well plates. On the day of the experiment, cells were washed and incubated with 100 μg of IgG, either alone or in the presence of blocking agents, at different time points to distinguish between specific and nonspecific uptake. 61 The cells were incubated with either [Cu]Cu or [Cu]Cu radiotracer. At each time point, the medium containing unbound (free) radiotracer was removed and subsequently 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 × 5 min to detach the cell surface-bound radiotracer (acid release). Subsequently, cells containing internalized radiotracer were detached with 1 M NaOH at 37 °C and collected for measurement. The amount of specific cell surface binding and internalized radiotracer is expressed as a percentage of the total radioactivity delivered after subtracting nonspecific values.

[0446] [ 61 Cu]Cu-DOTAGA-PSMA-I&T and [ 61 Cu]Cu-NODAGA-PSMA-I&T (0.5 nM) was evaluated in LNCaP cells, and their [ 68 Nonspecific binding was determined using 2-(phosphonomethyl)-pentanedioic acid (2-PMPA, 10 μM) compared to its Ga]Ga counterpart (Figure 14).

[0447] [ 61 Cu]Cu-DOTA-TOC and [ 61 Cu]Cu-NODAGA-TOC (2.5 nM) was evaluated in HEK-SST2 cells, and their [ 68 Nonspecific binding was determined using somatostatin-14 (SS-14, 25 μM).

[0448] 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) was evaluated.

[0449] The internalized and cell surface bound fractions of the radiotracers tested are reported in Tables 19, 20 and 21.

[0450] 68 relative to the Ga counterpart 61 Cellular uptake and distribution of Cu-labeled PSMA-I&T constructs between the cell surface (cell membrane-bound) and internalized fractions (Table 19). Values ​​are expressed as % of delivered radioactivity and refer to specific uptake calculated after subtracting the nonspecific value (measured in the presence of 10 μM 2-PMPA) from the total value (specific = total - nonspecific). [Table 29]

[0451] 61 Cu-labeled PSMA radiotracer showed time-dependent uptake in PSMA-expressing cells, with approximately equal distribution between the cell surface (membrane) and internalized fractions at 37°C. 61 Cu]Cu-NODAGA-PSMA-I&T 61 Cu]Cu-DOTAGA-PSMA-I&T showed slightly lower, but not significantly lower, cell surface binding and internalization than Cu-DOTAGA-PSMA-I&T. 61 The cellular uptake of Cu-labeled PSMA radiotracer constructs was measured using their 68 The above findings collectively lead to the conclusion that PSMA-mediated cellular uptake in vitro is not hindered by exchanging the chelator or radionuclide.

[0452] Table 20. 61 Cu-labeled somatostatin analogs versus their 68 Cellular uptake and distribution between the cell surface (cell membrane-bound) and internalized fractions of Ga counterparts. Values ​​are expressed as % of delivered radioactivity and refer to specific uptake calculated after subtracting the nonspecific value (measured in the presence of 25 μM somatostatin-14) from the total value (specific = total - nonspecific). [Table 30]

[0453] 61 The Cu-labeled TOC radiotracer was almost completely internalized in SST2-expressing cells at 37°C in a time-dependent manner, with only a small amount remaining on the cell surface (plasma membrane). 61 The present observations between Cu radiotracers and their corresponding 68 Comparison with the Ga counterpart is consistent with the findings above for the PSMA constructs. Table 21. Cell surface (cell membrane bound) 61 Cellular uptake and distribution of Cu-labeled FAPI analogs to and from the internalized fraction. Values ​​are expressed as % of delivered radioactivity and refer to specific uptake calculated after subtracting the nonspecific value (measured in the presence of the FAP-nonexpressing cell line HT-1080.wt) from the total value (specific = total - nonspecific). [Table 31]

[0454] 61 The Cu-labeled FAP radiotracer was rapidly and almost completely internalized in cells expressing human FAP at 37°C, with only negligible amounts remaining on the cell surface (plasma membrane).

[0455] Example 7 - Tumor xenografts Four to six 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 mixture of culture medium and Matrigel, HEK-SST2 cells (107 cells / 100 µL) suspended in sterile phosphate-buffered saline, or dual HT-1080.hFAP cells (5 x 106 cells / 100 µL, right shoulder) and HT-1080.wt cells (5 x 106 cells / 100 µL, left shoulder). Tumors were allowed to grow for 1 to 3 weeks before the start of the experiment. LNCaP xenografts were used for evaluation of PSMA-based radiotracers, SST2 xenografts were used for somatostatin-based radiotracers, and HT-1080.hFAP and HT-1080.wt were used for FAP inhibitor-based radiotracers.

[0456] Example 8 - PET / CT Imaging Tumor xenograft mice were injected intravenously into the tail vein with the radiotracer to be tested. For LNCap xenografts, 100 μL / 400 pmol / 4–8 MBq 61 Cu-labeled PSMA radiotracer was injected into HEK-SST2 xenografts at 100 μL / 200 pmol / 3–5 MBq. 61 Cu-labeled somatostatin radiotracer was injected into the HT-1080 xenografts at 100 μL / 500 pmol / 10–12 MBq. 61A Cu-labeled FAP inhibitor radiotracer was injected. Mice were anesthetized with 1.5% isoflurane, and dynamic PET scans were acquired 1 hour after injection of the radiotracer. Mice were euthanized with CO2 at 4 hours postoperatively. The bladder was mechanically emptied, and static PET scans were acquired for 30 minutes. PET images were acquired using a β-CUBE PET scanner system (MOLECUBES, Gent, Belgium), attenuation-corrected, and reconstructed using VivoQuant software version 4.0. CT scans were performed in the head-on supine position using a NanoSPECT / CT™ scanner (Bioscan Inc.). First, a topogram and helical CT scan of the whole mouse were acquired using the following parameters: X-ray tube current: 177 μA, X-ray tube voltage: 45 kVp, 90 seconds, and 180 frames per rotation, with a pitch of 1. CT images were reconstructed using CTReco (version r1.146) with a standard filtered backprojection algorithm (accurate cone beam) and post-filtering (RamLak, 100% frequency cutoff) to obtain a pixel size of 0.2 mm. Co-registered PET / CT images were visualized using maximum intensity projection (MIP) with InVivoScope (version 1.43, Bioscan Inc.). The results are shown in the example below.

[0457] Example 9 - Biodistribution study Quantitative biodistribution studies were performed in tumor xenografted mice after intravenous injection into the tail vein of the tested radiotracers as follows: 61 Cu]Cu-DOTAGA-PSMA-I&T and [ 61 Cu]Cu-NODAGA-PSMA-I&T was injected into LNCaP xenografts at an injection volume of 100 μL / 200 pmol / 1.5–3.5 MBq, [ 61 Cu]Cu-NODAGA-TOC or [ 61 Cu]Cu-DOTA-TOC was administered to HEK-SST2 xenografts at an injection volume of 100uL / 200pmol / 1.5-4.5MBq, [ 61 Cu]Cu-NODAGA-F1,[ 61 Cu]Cu-NODAGA-F3,[ 61Cu]Cu-NODAGA-F2,[ 61 Cu]Cu-NODAGA-F4 or [ 61 Cu[Cu]Cu-NODAGA-FAPI-46 was injected into HT-1080.hFAP and HT-1080.wt xenografts at a dose of 100 μL / 500 pmol / 0.8–1.2 MBq. Mice were randomly assigned to groups and euthanized 1 and 4 h after injection. Organs of interest were collected, rinsed, blotted, weighed, and counted in a gamma counter. Results are expressed as the percentage of injected radioactivity per gram (%IA / g) and represent the mean ± standard deviation of n = 4–8 mice per group. They were obtained by extrapolation from counting aliquots obtained from the solution injected as a standard.

[0458] The results are shown in Tables 22, 23, 24A, 24B, and 24C. [Table 32]

[0459] [ 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 kidneys and salivary glands. 61 Cu]Cu-NODAGA-PSMA-I&T 61 Compared to [Cu]Cu-DOTAGA-PSMA-I&T, it also showed higher tumor uptake and higher kidney uptake, followed by undesirably higher uptake in the liver, stomach, intestine, and blood, which contributed to an overall higher background. 61 Cu]Cu-NODAGA-PSMA-I&T demonstrated superiority due to higher tumor uptake and improved tumor-to-nontumor organ ratios (except tumor-to-kidney at 4 hours). Between the two time points investigated, 1 hour and 4 hours post-injection, 4 hours was shown to be advantageous due to a significant improvement in tumor-to-background ratio (see Figure 12). [Table 33]

[0460] [ 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 excretion via the kidney. 61 Cu]Cu-NODAGA-TOC 61 Compared to [Cu]Cu-DOTA-TOC, [Cu]Cu-DOTA-TOC exhibits higher kidney uptake, followed by undesirably high uptake in the liver, stomach, pancreas, and intestine, as well as blood, which contributes to an overall higher background. 61 Cu]Cu-NODAGA-TOC demonstrated superiority due to improved tumor-to-nontumor organ ratios (tumor to non-kidney). Between the two time points studied, 4 hours post-injection was shown to be advantageous compared to 1 hour due to significantly improved tumor-to-background ratios.

[0461] The observations in PSMA and SST2 xenografts combined with different targeting moieties [ 61 Cu]Cu-DOTAGA or [ 61 Cu]Cu-DOTA chelate 61 Advantages of Cu-NODAGA chelate and its routine clinical use 68 Ga (half-life 68 min) 61 The advantage of Cu (half-life 3.33 hours) is consistent and representative by imaging at 4 hours instead of 1 hour.

[0462] [ 61 Cu]Cu-NODAGA-F1 showed high accumulation in FAP-positive (HT-1080.hFAP) tumors and mouse FAP-positive tissues, such as synovial tissue of joints (e.g., the joint associated with the femur). [Table 34] [Table 35] [Table 36]

[0463] [ 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 tissue of joints (e.g., the joint associated with the femur).

[0464] Example 10 - Specificity Test [ 61 Cu]Cu-NODAGA-PSMA-I&T and [ 61 The specificity of Cu]Cu-DOTAGA-PSMA-I&T was evaluated in LNCaP xenograft mice, which were first injected with 1.3 μmol (300 μg) of 2-phosphonomethylpentanedioic acid (2-PMPA) as a blocking agent, followed by the injection of a radioactive tracer, e.g., [ 61 Cu]Cu-DOTAGA-PSMA-I&T (100μL / 400pmol / 4~8MBq) or [ 61 Cu]Cu-NODAGA-PSMA-I&T (100 μL / 400 pmol / 4-8 MBq) was injected. PET / CT images were acquired 1 hour after injection as described in Example 8. Additionally, free (uncomplexed) 61 To assess the systemic distribution of Cu, 61 PET / CT images of the xenografts were acquired after injection of [Cu]CuCl (100 μL / 7 MBq). The results are shown in Figure 10, panels A and B. L = liver; K = kidney; T = tumor; Bl = bladder; I = intestine.

[0465] In PSMA-positive tumors and kidneys in xenografts pre-injected with 2-PMPA 61 Cu]Cu-NODAGA-PSMA-I&T and [ 61 The significantly lower uptake of Cu]Cu-DOTAGA-PSMA-I&T indicates PSMA-mediated uptake (specificity) (Figure 12, panels A and B). 61 PET / CT images of Cu (Figure 12, panel C) showed accumulation in the abdomen, especially in the liver and intestine, which is consistent with [ 61 Cu] is comparable to the uptake seen in PET / CT images of Cu-DOTAGA-PSMA-I&T (in addition to tumor and kidney), but [ 61 The systemic distribution of Cu-NODAGA-PSMA-I&T is not comparable to that of Cu]Cu-NODAGA-PSMA-I&T (Figure 11, panels A and B). 61 Cu]Cu-NODAGA-TOC (Figure 13, panels C and D) or [ 61 Cu]Cu-(R)-NODAGA-LM3 (Figure 13, panels E and F). 61 Similar observations were made for Cu]Cu-DOTA-TOC (Figure 13, panels A and B). 61 This direct comparison is based on the 61 Cu]Cu-DOTAGA and [ 61 In contrast to the poor in vivo stability of the [Cu]Cu-DOTA radiotracer, 61 [Cu]Cu-NODAGA is an indication of the high in vivo stability and therefore superiority of the radiotracer.

[0466] Example 11 - Pharmacokinetics in non-tumor-bearing mice [ 61 / 64 Cu]Cu-NODAGA-PSMA-I&T (Table 25) and [ 61 Cu] / [ 64 Pharmacokinetic studies of Cu]Cu-NODAGA-TOC (Table 26) were performed in healthy female BALB / c mice from 1 to 24 hours after injection of 100 μL / 200 pmol / 4 MBq of the corresponding radiotracer. 61 Cu (half-life 3.33 h) was used at 1 and 4 h time points;64 Cu (half-life 12.7 hours) was used at 12 and 24 hours. Biodistribution at the study time points was performed as described in Example 9. Because biodistribution in nude mice was similar to that in healthy mice, the data were combined with results obtained from the xenograft groups at 1 and 4 hours pi. Results were presented as described in Example 10. [Table 37]

[0467] [ 61 / 64 [Cu]Cu-NODAGA-PSMA-I&T had rapid blood clearance and high accumulation in the kidney due to the excretion pathway and expression of PSMA. Other organs with significant uptake were the adrenal glands, spleen, and intestine. Within 24 hours, the radiotracer was washed out from all organs except the kidney. [Table 38]

[0468] [ 61 / 64 Cu]Cu-NODAGA-TOC had very fast blood clearance and was almost completely excreted from the body within 24 hours.

[0469] Example 12-[ 61 In vivo comparison of Cu]Cu-NODAGA radiotracer with reference compounds [ 61The biodistribution of the Cu]Cu-NODAGA radiotracer was compared with that of a reference compound used in patients under identical experimental conditions. Mice were randomly divided into groups, injected with the radiotracer under investigation, and euthanized 1 and 4 hours after injection of the radiotracer under investigation. Organs of interest were collected, rinsed, blotted, weighed, and counted in a gamma counter. Results are expressed as percent injected radioactivity per gram (% IA / g) and represent the mean ± standard deviation of all mice per group, obtained by extrapolation from counting aliquots obtained from the solution injected as a standard. Table 27 and Figures 31 and 32 show the [ 61 Cu]Cu-NODAGA-PSMA-I&T (100μL / 200pmol / 1.5~3.5MBq), versus [ 68 Ga]Ga-PSMA-11 (100 μL / 200 pmol / 3–5 MBq), versus [ 18 F]PSMA-1007 (100 μL / 70 pmol / 15 MBq) and Table 28 shows the [ 61 Cu]Cu-NODAGA-TOC vs. [ 68 33 and 34 show a direct comparison of [Ga]Ga-DOTA-TOC 1 hour after injection. 61 Cu]Cu-NODAGA-LM3 pair [ 68 A direct comparison of Ga]Ga-DOTA-TOC is shown. [Table 39]

[0470] [ 61 Cu]Cu-NODAGA-PSMA-I&T is the reference radiotracer used in the clinic 1 hour after injection [ 68 Ga]Ga-PSMA-11 (Figure 31). 61 Cu]Cu-NODAGA-PSMA-I&T offers the possibility of imaging 4 hours after injection with a significantly increased tumor-to-background ratio, which is expected to significantly improve image contrast and enhance diagnostic sensitivity. 61Cu]Cu-NODAGA-PSMA-I&T is also another reference radiotracer used in the clinic [ 18 F]PSMA-1007 at 1 and 4 hours p.i., with some exceptions. 18 At a later time point (4 hours pi), [F]PSMA-1007 showed higher and more sustained splenic uptake. 61 Cu]Cu-NODAGA-PSMA-I&T is clinically used [ 18 F]PSMA-1007 (10.7 ± 3.3 vs. 6.28 ± 2.19% IA / g, p = 0.0145), and has a better tumor-to-background (tumor-to-blood and tumor-to-muscle) ratio. [Table 40]

[0471] [ 61 Cu]Cu-NODAGA-TOC is the reference radiotracer used in clinics [ 68 It compares well with Ga]Ga-DOTA-TOC, providing a higher tumor-to-background ratio at 1 hour post-injection, and further improving at 4 hours post-injection (see Figure 34).

[0472] Overall, [ 61 The Cu]Cu-NODAGA radiotracer was shown to be effective against [ 61 Cu]Cu-DOTAGA or [ 61 Compared to the [Cu]Cu-DOTA radiotracer, their sustained tumor uptake and high in vivo stability (see Example 10), as well as their lower background (see Examples 8 and 9), make them suitable for 4-hour imaging. 61 For improved image contrast when using Cu]Cu-NODAGA chelates in combination with targeting moieties, 68 This compares favorably with the 1 hour routinely performed in Ga.

[0473] Example 13: Synthesis of FAP inhibitors 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) Step 1: (S)-6-amino-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)quinoline-4-carboxamide (A) [ka]

[0474] The two precursors (purchased from AstaTech) were dissolved in DMF along with HATU, followed by the addition of DCM. DIPEA was added dropwise, and the reaction was monitored by LC / MS. The reaction was complete in less than 1 h. The crude product was concentrated, diluted with water / ACN 85:15, and directly purified by HPLC (LCMS-2020 Shimadzu system equipped with a Gemini C-6 Phenyl column (10 × 250 mm, 5 μm particle size)). The gradient used was 5–80% solvent B in 15 min (A = HO [0.1% TFA], B = ACN [0.1% TFA]), flow rate 5.0 mL / min), affording A as a pure red powder (38 μg, 84% yield).

[0475] 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) [ka]

[0476] (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 was mixed overnight and confirmed by LC / MS. The crude product was directly purified by HPLC (LCMS-2020 Shimadzu system equipped with a Gemini C-6 Phenyl column (10 x 250 mm, 5 µm particle size)). The gradient used was 5 to 80% solvent B in 8 min (A = HO [0.1% TFA], B = ACN [0.1% TFA]), flow rate 5.0 mL / min), affording B as a yellow powder (32.7 µg, 68% yield).

[0477] Step 3: (S)—N1-(2-aminoethyl)-N4-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)succinimide (F1) [ka]

[0478] (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 was stirred overnight and confirmed by LC / MS. The crude product was directly purified by HPLC (5-80% in 8 min) to give F1 as a yellow powder (32.7 μg, 68% yield).

[0479] 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) F2 was prepared as shown in Scheme 2: Scheme 2 [ka]

[0480] Step 1: To a mixture of compound A (4.17 g, 22.2 mmol) in MeOH (84.0 mL) was added SOCl2 (26.4 g, 222 mmol, 16.1 mL) in one portion at 0-5 °C under N2. The reaction 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 stirred at 75 °C for 12 h. SOCl2 (26.4 g, 222 mmol, 16.1 mL) was added to the mixture and stirred at 75 °C for 12 h. SOCl2 (13.2 g, 111 mmol, 8.04 mL) was added to the mixture and stirred at 75 °C for 12 h. LC-MS showed that one major peak with the desired mass was detected. The mixture was concentrated in vacuo. The crude product was triturated with MeCN (300 mL) at 20 °C for 1 h to give compound B (7.05 g, crude) as a brown solid. LC-MS (LCMS-2020 Shimadzu system equipped with a Gemini C-6 Phenyl column (3.5 × 250 mm, 5 μm particle size). The gradient used was 5–80% solvent B (A = HO [0.1% TFA], B = ACN [0.1% TFA]) over 8 min, flow rate 1.0 mL / min, product: RT = 1.262 min).

[0481] Step 2: To solution B (7.02 g, 34.7 mmol) in MeOH (100 mL) and BocO (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 was consumed, with one peak of the desired MS signal. The mixture was concentrated in vacuo. Purification by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1, compound C Rf = 0.35) afforded compound C (4.36 g, 41.5% yield) as a brown solid.

[0482] Step 3: To a solution of compound C (3.36 g, 11.1 mmol) in DMF (84.0 mL), NaH (778 μg, 19.5 mmol, 60% purity) was added portionwise at 0 °C, and the mixture was stirred at 25 °C for 20 min. MeI (3.94 g, 27.8 mmol) was added to the reaction mixture at 25 °C, and the mixture was stirred at 25 °C for 2 h. LCMS (ET60385-17-P1A3, product RT = 0.562 min) showed that compound C was consumed, and one peak of 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 (4.78 g, crude) as a brown solid.

[0483] Step 4: To a solution of compound D (4.78 g, 15.1 mmol) in DCM (50.0 mL), TFA (8.61 g, 75.5 mmol) was added dropwise, and the mixture was stirred at 25 °C for 12 h. LCMS showed that compound D was consumed, with one peak of the desired MS. The reaction mixture was quenched with saturated NaHCO (50.0 mL) and extracted with DCM (3 × 40.0 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 1 / 1, product Rf = 0.40) afforded compound E (2.51 g, 76.8% yield) as a brown solid.

[0484] 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 hours. LCMS showed that compound E was consumed, and one peak of the desired MS was detected. The mixture was concentrated in vacuo to give compound F (716 μg, crude) as a brown solid.

[0485] Step 6: To a solution of compound F (716 μg, 2.26 mmol) in DMF (7.00 mL), 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) were added, and the reaction mixture was stirred at 25 °C for 12 hours. LCMS showed that compound F was consumed, and one peak of the desired MS was detected. The reaction mixture was quenched with saturated NaHCO (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.

[0486] 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), and the mixture was stirred at 110 °C for 4 hours. LCMS showed that compound G was consumed, with one peak of the desired MS. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*100 mm#10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 1% to 30%, 20 min) to give compound H (647 μg, 50.1% yield) as an off-white solid.

[0487] Step 8: To a solution of compound H (617 μg, 1.39 mmol) in DMF (6.00 mL), DIEA (717 μg, 5.55 mmol), HATU (791 μg, 2.08 mmol), and compound 6-1 (587 μg, 2.08 mmol, 80% purity, HCl) were added, and the mixture was stirred at 25 °C for 1 hour. LCMS showed that compound H was consumed, and one peak of the desired MS was detected. The reaction mixture was quenched with saturated NaHCO (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.

[0488] Step 9: To a solution of compound I (2.70 g, 4.39 mmol) in DCM (10.0 mL), TFA (41.5 g, 364 mmol) was added, and the mixture was stirred at 25 °C for 1 h. LCMS (ET60385-61-P1A4, product RT = 0.490 min) showed that compound I was consumed, and one peak of 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#10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 5% to 35%, 20 min) to give compound F2 (260 μg, 11.1% yield, 97.3% purity) as a brown solid. LCMS (LCMS-2020 Shimadzu system equipped with a Gemini C-6 Phenyl column (3.5 × 250 mm, 5 μm particle size). The gradient used was 5–80% solvent B in 8 min (A = HO [0.1% TFA], B = ACN [0.1% TFA]), flow rate 1.0 mL / min, product RT = 0.493 min). 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) [ka]

[0489] (S)-4-((4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoic acid, HATU and amine were dissolved in DCM and DMF. DIPEA was added dropwise to check the reaction. When all coupling had occurred, the crude product was concentrated slightly and then TIPS was added. TFA was added dropwise and the mixture was checked by LC / MS until completion. The crude product (F3) was used directly.

[0490] 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) F4 was prepared as shown in Scheme 3: Scheme 3 [ka]

[0491] Step 1: To a mixture of compound J (10.0 g, 53.7 mmol) in DCM (70.0 mL) was added tetrahydrofuran-2,5-dione (5.37 g, 53.7 mmol). The mixture was stirred at 20° C. for 2 hours. TLC (dichloromethane / methanol / AcOH=9 / 1 / 0.01, compound J Rf=0.0) indicated that the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane / methanol=100 / 1, 9 / 1) to give compound K (4.75 g, 30.9% yield) as a white solid.

[0492] Step 2: To a solution of compound L (300 μg, 1.39 mmol) in EtOAc (10.0 mL), DIEA (537 μg, 4.16 mmol), compound K (476 μg, 1.66 mmol), and T3P (11.2 g, 17.7 mmol, 50% purity) were added, and the reaction mixture was stirred at 25 °C for 0.5 h. LCMS showed that compound L was consumed, with one peak of the desired MS. The reaction mixture was then diluted with EtOAc (20.0 mL) and washed with water (60.0 mL), saturated NaHCO3 (60.0 mL), and brine (20.0 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to give compound M (716 μg, crude) as a brown oil.

[0493] Step 3: To a solution of compound M (716 μg, 1.48 mmol) in Py (20.0 mL), LiI (3.96 g, 29.5 mmol) was added, and the mixture was stirred at 110 °C for 4 h. LCMS showed that compound M was consumed, with one peak of the desired MS. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*100 mm#10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 1% to 30%, 20 min) to give compound N (460 μg, 64.4% yield, 97.4% purity) as an off-white solid. LCMS (LCMS-2020 Shimadzu system equipped with a Gemini C-6 Phenyl column (3.5 × 250 mm, 5 μm particle size). The gradient used was 5–80% solvent B in 8 min (A = HO [0.1% TFA], B = ACN [0.1% TFA]), flow rate 1.0 mL / min, product RT = 0.596 min).

[0494] Step 4: To a solution of compound N (460 μg, 977 μmol) in DMF (5.00 mL), DIEA (505 μg, 3.91 mmol), PYBOP (763 μg, 1.47 mmol), and compound 6-1 (330 μg, 1.47 mmol, HCl) were added, and the mixture was stirred at 25 °C for 1 h. LCMS showed that one peak of the desired MS was detected. The reaction mixture was quenched with saturated NaHCO (15.0 mL), extracted with DCM (25.0 mL × 3), and washed with brine (15.0 mL). The organic layer was dried over NaSO, filtered, and concentrated in vacuo to give compound O (2.10 g, crude) as a brown oil.

[0495] Step 5: To a solution of compound O (2.10 g, 3.27 mmol) in DCM (10.0 mL), TFA (15.4 g, 135 mmol) was added, and the mixture was stirred at 25 °C for 1 hour. LCMS showed that compound O was consumed, and one peak of the desired MS was detected. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250*70 mm#10 um; mobile phase: [water (NH4HCO3)-ACN]; B%: 0% to 40%, 20 min) to give compound F4 (196 μg, 11.0% yield) as an off-white solid. Synthesis of FAPI-46

[0496] FAPI-46 was prepared as shown in Scheme 4: Scheme 4 [ka]

[0497] FAPI-46 can also be prepared according to the methods described in WO 2019 / 154886. Example 14: Synthesis of FAPI-NODAGA targeted chelator constructs 5.1.16. Synthesis of 2,2'-(7-((R)-1-carboxy-4-((2-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanamido)ethyl)amino)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid ((R)-NODAGA-F1) [ka]

[0498] To the crude (S)-N1-(2-aminoethyl)-N4-(4-((2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)succinimide (F1) solution, DIPEA was added dropwise to neutralize the TFA. HATU and NODAGA-Tris(tBu) were then added dropwise as a DMSO solution (150 μL). The reaction was complete after a few minutes. The crude product was concentrated and purified via HPLC. To the pure material, DCM, TIPS, and TFA were added, and the reaction was left to complete for 1 day. Purification via HPLC afforded 15.8 μg of (R)-NODAGA-F1 as a pale yellow powder (yield: 51%). 5.1.17. Synthesis of 2,2'-(7-((R)-1-carboxy-4-((2-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)(methyl)amino)-4-oxobutanamido)ethyl)amino)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid ((R)-NODAGA-F2) [ka]

[0499] Step 1: To a solution of compound F2 (80.0 μg, 155 μmol) in DMF (1.00 mL), DIEA (80.2 μg, 620 μmol), HATU (121 μg, 232 μmol), and NODAGA-Tris(tBu) (101 μg, 186 μmol) were added, and the mixture was stirred at 25 °C for 1 h. LCMS showed that compound F2 was consumed, with one peak of the desired MS. The reaction mixture was quenched with saturated NaHCO3 (4.00 mL), extracted with DCM (10.0 mL × 3), and washed with brine (10.0 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give R (310 μg, crude) as a brown oil.

[0500] Step 2: To a solution of compound R (310 μg, 297 μmol) in TFA (1.29 g, 11.3 mmol) at 25 °C, the mixture was stirred at 25 °C for 1 h. LCMS showed that compound R was consumed, and one peak of the desired MS was detected. The mixture was concentrated in vacuo. The crude products ET60385-73 (220 μg, crude) and ET60385-78 (206 μg, crude) were combined for further purification. The residue was purified by preparative HPLC (column: C18-1 150*30 mm*5 μm; mobile phase: [water (TFA)-ACN]; B%: 5% to 35%, 20 min) to give (R)-NODAGA-F2 (10.01 μg, yield 3.30%, purity 96.9%, TFA) as a brown solid. LCMS (ET60385-73-P1Z1, product RT=1.610 min). 5.1.18. Synthesis of 2,2'-(7-((R)-1-carboxy-4-(4-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)amino)-4-oxobutanoyl)piperazin-1-yl)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid ((R)-NODAGA-F3) [ka]

[0501] To the crude (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-oxo-4-(piperazin-1-yl)butanamido)quinoline-4-carboxamide (F3) solution, DIPEA was added dropwise to neutralize the TFA. HATU and NODAGA-Tris(tBu) were then added dropwise as a DMSO solution (150 μL). The reaction was complete after a few minutes. The crude product was concentrated and purified via HPLC. To the pure material, DCM, TIPS, and TFA were added, and the reaction was left to complete for 1 day. Purification via HPLC afforded 15.8 μg of (R)-NODAGA-F3 as a pale yellow powder (yield: 26%). 5.1.19. Synthesis of 2,2'-(7-((R)-1-carboxy-4-(4-(4-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)(methyl)amino)-4-oxobutanoyl)piperazin-1-yl)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid ((R)-NODAGA-F4) [ka]

[0502] Step 1: To a solution of compound F4 (40.0 μg, 73.8 μmol) in DMF (0.50 mL), DIEA (9.55 μg, 73.8 μmol), HATU (57.6 μg, 110 μmol), and NODAGA-Tris(tBu) (48.1 μg, 88.6 μmol) were added. The mixture was stirred at 25 °C for 1 hour. LCMS showed that one peak of the desired MS was detected. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 50%-90%, 8 min) to give compound S (28.0 μg, 35.5% yield) as a white solid.

[0503] Step 2: Compound S (28.0 μg, 26.2 μmol) was placed in a microwave tube in HFIP (4.41 μg, 26.2 μmol). The sealed tube was heated in a microwave at 100° C. for 48 hours. LCMS showed that compound S was consumed, with one peak of the desired MS. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30 mm*3 um; mobile phase: [water (TFA)-ACN]; B%: 5% to 30%, 8 min) to give (R)-NODAGA-F4 (9.01 μg, 36.9% yield, 96.6% purity, TFA) as an off-white solid. LCMS (ET56076-48-P1Z2, product RT=1.640 min) 5.1.20. Synthesis of 2,2'-(7-(1-carboxy-4-(4-(3-((4-((2-((S)-2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)carbamoyl)quinolin-6-yl)(methyl)amino)propyl)piperazin-1-yl)-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODAGA-FAPI-46) [ka]

[0504] (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-(4-oxo-4-(piperazin-1-yl)butanamide)quinoline-4-carboxamide, (R)-NODAGA(tris)tBu, and HATU were dissolved in DCM + 100 μL of DMF. DIPEA was added dropwise, and the reaction was stirred for 2 h until complete (confirmed via LC / MS, 15-80% in ACN). When no starting material remained and only a peak related to the product mass was observable (m / z = 1025), TIPS and TFA (600 μL) were added. After 48 h, the reaction was complete. The crude product was purified by HPLC (10-65% CAN in 15 min, rt = 9.5) to give 6.8 μg of a red powder (yield: 36%).

[0505] Example 15: Radiolabeled FAP-targeted chelator constructs [ 61 Cu]Cu-NODAGA-F1 and 61 Cu-NODAGA-F3 An aliquot of the conjugate (3–6 nmol, 1 μg / mL in water) was diluted with 0.25–0.30 mL of ammonium (or sodium) acetate (0.5 M pH 8), followed by 0.1–0.7 mL of [ 61[Cu]CuCl2 was added (70-240 MBq). The reaction mixture was incubated at room temperature (approximately 20-25 °C) for 15 minutes. The pH of the reaction was 5-6. Quality control was performed by reversed-phase high-performance liquid chromatography (RP-HPLC) coupled to a radio-detector (radio-HPLC). The radio-HPLC results are shown in Table 29 below.

[0506] [ 61 Cu]Cu-NODAGA-F2 and [ 61 Cu]Cu-NODAGA-F4 61 Preparation of Cu-labeled conjugates involves dissolving 1.5–3 nmol of the corresponding conjugate (as a 1 μg / mL solution) in 125–300 μL of ammonium acetate (0.5 M, pH 8) in 50–200 μL of [ 61 The reaction was performed by incubation with [Cu]CuCl2 (33–70 MBq). A pH check was performed to ensure the necessary conditions for the reaction (pH ≥ 5). The reaction mixture was incubated at room temperature for 10 min. Quality control and stability testing were performed by radio-HPLC on a Shimadzu SCL-40 connected to a GABI radioactivity-HPLC-flow monitor γ-spectrometer (Elysia raytest, Straubenhardt, Germany). Analysis of the radioligand was performed using a Phenomenex Jupiter Proteo C12 (90 Å, 250 × 4.6 mm) column with a gradient of 15–80% B over 8 min (A = HO [0.1% TFA], B = ACN [0.1% TFA]) at a flow rate of 1 mL / min. The radio-HPLC results are shown in Table 29 below. [Table 41]

[0507] All conjugates 61 Labeling with Cu resulted in high radiochemical purity. 61 No further purification steps were required to remove Cu from the reaction mixture, allowing direct use of the formed radiotracer.

[0508] Example 16: Partition coefficient (Log D) of FAPI radiotracer The lipophilicity / hydrophilicity of the radioactive tracer was assessed by determining the partition coefficient (D) between the aqueous and organic phases according to the "shake flask" method and expressed as log D (pH = 7.4). A pre-saturated mixture of 500 μL of 1-octanol and 500 μL of PBS pH 7.4 (phosphate-buffered saline) was added to a pre-lubricated Eppendorf tube. A 10 μL aliquot of 10 pmol of radioligand was added to this mixture, shaken for 30 minutes, and then centrifuged at 3000 rcf for 1...

Claims

1. 1. A composition comprising a radioactive tracer, a chelating moiety; and a copper radionuclide (*Cu) chelated by said chelating moiety; a targeting moiety covalently attached to said chelating moiety; A composition comprising:

2. A compound is provided, said compound having formula A: 【Chemical 1】 During the ceremony, 【Chemistry 2】 is the chelating moiety, *Cu ６１ Cu, ６２ Cu, ６４ Cu or ６７ Cu, L is a bond or a linker moiety; V is the targeting moiety; n is an integer from 1 to 10, preferably 1; The composition of claim 1.

3. 3. The composition of claim 1, wherein the Cu is in the (II) oxidation state.

4. 4. The composition of any one of claims 1 to 3, having a molar radioactivity in the range of 1 to 250 MBq / nmol and / or a radiochemical purity of 91% or greater.

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

6. The composition of any one of claims 1 to 5, wherein one or more of the binding moieties is selected from a thiol group, an amine group, and a carboxylate group.

7. The composition of claim 6 , wherein one or more of the binding moieties is a tertiary amine.

8. The composition of any one of claims 1 to 7, wherein the chelating moiety comprises six binding elements selected from a combination of amine and carboxylate groups.

9. The chelating moiety is according to Formula 1: 【Chemistry 3】 In the formula, R １ , R ２ and R ３ are individually C ２－６ alkyl, optionally oxo, thiol, hydroxyl, C, including its deprotonated variants upon chelation with Cu １－３ Alkoxy, C １－３ Carboxy, and C １－３ substituted with one or more substituents selected from alkylthiols; R １ , R ２ and R ３ or at least one of the methylene carbons forming the nitrogen ring comprises the point of attachment to the linker moiety (when L is a linker moiety) or the targeting moiety (when L is a bond).

10. The chelating moiety is according to Formula 1′ or Formula 1′a: 【Chemistry 4】 【Chemistry 5】 During the ceremony, 【Chemistry 6】 represents the point of attachment to the linker moiety (when L is a linker moiety) or the targeting moiety (when L is a bond).

11. The chelating moiety is according to Formula 2, 2' or Formula 2'2'a: 【Chemistry 7】 【Chemistry 8】 In the formula, X １ , X ２ and X ３ * -OH, -NH, including their deprotonated variants upon chelation with Cu ２ -SH; The composition of claim 10, wherein any methylene is optionally substituted with oxo, thiol, or hydroxyl.

12. The chelating moiety is according to formula 2i, 2'i, 2ii, or 2iii: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 The composition of claim 11.

13.

13. According to formula II or II': 【Chemistry 14】 【Chemistry 15】 In the formula, X １ , X ２ and X ３ * -OH, -NH, including its deprotonated variants upon chelation with Cu ２ and -SH; any methylene is optionally substituted with oxo, thiol, or hydroxyl; 【Chemistry 16】 represents the point of attachment to the linker moiety (when L is a linker moiety) or the targeting moiety (when L is a bond).

14.

17. According to Formula II: 【Chemistry 18】 X １ , X ２ and X ３ * -OH, -NH, including its deprotonated variants upon chelation with Cu ２ and -SH; any methylene is optionally substituted with oxo, thiol, or hydroxyl; 【Chemistry 19】 represents the point of attachment to the linker moiety (when L is a linker moiety) or the targeting moiety (when L is a bond).

15.

20. According to formula IIi, II'i, IIii or IIiii: 【Chemical formula 21】 【Chemical 22】 【Chemical 23】 【Chemistry 24】 15. The composition of claim 14.

16. The chelating moieties include: DOTAGA (1,4,7,10-tetraazacyclododecane, 1-(glutaric 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-cyclododec-1-yl-acetic acid), 3p-C-DEPA (2-[(carboxymethyl)][5-(4-nitrophenyl-1-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]pentan-2-yl)amino]acetic acid), TCMC (2-(4-isothiocyanobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamonylmethyl)-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-glutaric acid-4,7-acetic acid) (NOTAGA), 1,4,7-triazonane-1,4-diyl)diacetic acid DFO (desferoxamine), NETA ([4-[2-(bis-carboxymethylamino)-ethyl]-7-carboxymethyl-[1,4,7]triazonan-1-yl}acetic acid), TACN-™ (N,N',N",tris(2-mercaptoethyl)-1,4,7-triazacyclononane), Diamsar (1,8-diamino-3,6,10,13,16,19-hexaazabicyclo[6,6,6]eicosane, 3,6,10,13,16,19-hexaazabicyclo[6,6,6]eicosane, The composition according to any one of claims 1 to 15, wherein the hydroxybenzoic acid is selected from the group consisting of benzophenone-1,8-diamine (eicosane-1,8-diamine), Sara (1-N-(4-aminobenzyl)-3,6,10,13,16,19-hexazabicyclo[6.6.6]eicosan-1,8-diamine), AmBaSar (4-((8-amino-3,6,10,13,16,19-hexazabicyclo[6.6.6]icosan-1-ylamino)methyl)benzoic acid), and 4,4'-((3,6,10,13,16,19-hexazabicyclo[6.6.6]ico-san-1,8-diylbis(aza-nediyl))bis(methylene))dibenzoic acid (BaBaSar).

17. The chelating moiety is 2,2',2"-(1,4,7-triazonane-1,4,7-triyl)triacetic acid (NOTA); 2,2'((2-(,7-bis-(carboxymethyl)-1,4,7-triazonan-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-triazonane-1,4-diyl)diacetic acid (NODAGA); 2 17. The composition of claim 16, comprising: (4,7-bis(carboxymethyl)-1,4,7-triazonan-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 chelating moiety may be 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA); 2,2'-(7-(1-carboxy-4-oxopentyl)-1,4,7-triazonane-1,4-diyl)diacetic acid (NODAGA); 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)succinic acid (NODASA); (1,4 18. The composition of claim 17, comprising (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. 19. The composition of claim 18, wherein the chelating moiety comprises NOTA, NODASA, or NODAGA.

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

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

22. *Cu ６１ 22. The composition of claim 21, wherein the metal is Cu.

23. *Cu ６７ 22. The composition of claim 21, wherein the metal is Cu.

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

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

26. 25. The composition of claim 24, wherein the molecular target is a tumor-associated antigen (TAA).

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

28. 28. The composition of claim 27, wherein the targeting moiety comprises an L-lysine-urea-glutamate-based PSMA inhibitor.

29. 29. The composition of claim 28, wherein the targeting moiety comprises Lys-Urea-Glu (KuE).

30. 25. The composition of claim 24, wherein the targeting moiety comprises a peptide analog of somatostatin.

31. 25. The composition of claim 24, wherein the targeting moiety comprises a cyclic octapeptide analog of somatostatin.

32. 25. The composition of claim 24, wherein the targeting moiety comprises a fibroblast activation protein (FAP) inhibitor.

33. 36. The composition of 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. 25. The composition of claim 24, wherein the targeting moiety comprises D-Phe-c(Cys-Tyr-D-Trp-Lys-Thr-Cys)Thr(ol).

35. The targeting moiety is p-Cl-Phe-cyclo(D-Cys-Tyr-D-4-amino-Phe(carbamoyl)-Lys-Thr-Cys)D-Tyr-NH ２ 25. The composition of claim 24, comprising:

36. 25. The composition of claim 24, wherein the targeting moiety comprises Lys-urea-Glu (KuE), where 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-hexaazatritriacontane-1,3,7,26-tetracarboxylic acid.

37. 25. The composition of claim 24, comprising a radioactive tracer having the structure: 【Chemistry 25】

38. 25. The composition of claim 24, comprising a radioactive tracer having the structure: 【Chemical 26】

39. 25. The composition of claim 24, comprising a radioactive tracer having the structure: 【Chemical 27】

40. 25. The composition of claim 24, comprising a radioactive tracer having the structure: 【Chemical 28】

41. 25. The composition of claim 24, comprising a radioactive tracer having the structure: 【Chemical 29】

42. 25. The composition of claim 24, comprising a radioactive tracer having the structure: 【Chemistry 30】

43. 25. The composition of claim 24, comprising a radioactive tracer having the structure: 【Chemical 31】

44. 1. A method for generating an image of an object, comprising: Administering to the subject the composition according to any one of claims 1 to 21 and 24 to 43, wherein *Cu ６１ Cu; generating an image of at least a portion of the subject's body; A method comprising:

45. 45. The method of claim 44, wherein the image is generated using positron emission tomography (PET).

46. *Cu ６１ 46. ​​The method of claim 45, wherein the metal is Cu.

47. 45. The method of claim 44, wherein the image is generated using single photon emission computed tomography (SPECT).

48. *Cu ６７ 48. The method of claim 47, wherein the metal is Cu.

49. 1. A method for detecting a disease in a subject, comprising:

40. A method of administering to the subject a composition according to any one of claims 1 to 39, wherein *Cu is [ ６１ Cu]Cu; and detecting the localization of the radiotracer; determining the presence or absence of the disease based on the presence or absence of localization of the radioactive tracer; A method comprising:

50. 50. The method of claim 49, wherein the localization of the radiotracer is detected using positron emission tomography (PET).

51. *Cu ６１ 51. The method of claim 50, wherein the metal is Cu.

52. 50. The method of claim 49, wherein the localization of the radiotracer is detected using single photon emission computed tomography (SPECT).

53. *Cu ６７ 53. The method of claim 52, wherein the metal is Cu.

54. 54. The method of any one of claims 49 to 53, wherein the disease is selected from cancer, an inflammatory disease, an infectious disease and an immune disease.

55. 55. The method of claim 54, wherein the disease is selected from a cancer selected from neuroendocrine tumors, somatostatin receptor-expressing tumors such as prostate cancer and malignant meningioma, FAP-overexpressing epithelial cancers and their respective microenvironments, 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.

56. 55. The method of 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 carcinoma, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumors, oncogenetic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

57. 55. The method of claim 54, wherein the disease is selected from cardiovascular disease, liver fibrosis and cirrhosis, arthropathy, IgG4-related disease, pulmonary fibrosis and interstitial lung disease, Crohn's disease, tuberculosis, sarcoidosis, and periprosthetic joint infections.

58. 1. A method for monitoring or determining the effectiveness of cancer treatment in a subject suffering from cancer, comprising:

40. A method of administering to the subject a composition according to any one of claims 1 to 39 at an earlier and later time point, wherein *Cu is ６１ Cu; detecting localization of said radiotracer at both said earlier and said later time points; monitoring or determining the effectiveness of the cancer treatment by comparing the amount of localization at the later time point with the amount of localization at the earlier time point; A method comprising:

59. 59. The method of claim 58, wherein the localization of the radiotracer is detected using positron emission tomography (PET).

60. *Cu ６１ 60. The method of claim 59, wherein the metal is Cu.

61. 59. The method of claim 58, wherein the localization of the radiotracer is detected using single photon emission computed tomography (SPECT).

62. *Cu ６７ 62. The method of claim 61, wherein the metal is Cu.

63. 63. The method of any one of claims 58-62, wherein the earlier time point is before initiating the cancer treatment and the later time point is at least one month after initiating the cancer treatment.

64. 64. The method of claim 63, wherein the cancer is selected from somatostatin receptor-expressing tumors such as neuroendocrine tumors, prostate cancer, and malignant meningiomas; FAP-overexpressing epithelial cancers and their respective microenvironments, including non-small cell lung cancer, triple-negative breast cancer, colorectal cancer, gastric cancer, ovarian cancer, and pancreatic cancer.

65. 64. The method of 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 carcinoma, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumor, oncogenetic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

66. 1. A method for generating an image of an object, comprising: Administering to the subject the composition according to any one of claims 1 to 21 and 23 to 43, wherein *Cu ６７ Cu; generating an image of at least a portion of the subject's body using single photon emission computed tomography (SPECT); A method comprising:

67. 1. A method for monitoring the distribution and effect of a cancer treatment in a cancer patient, comprising: Administering to the subject the composition according to any one of claims 1 to 21 and 23 to 43, wherein *Cu ６７ Cu; detecting said localization of said radiotracer using SPECT; A method comprising:

68. 10. A method of providing radionuclide therapy to a cancer patient in need thereof, comprising administering to said patient an effective amount of the composition of any one of claims 1 to 21 and 23 to 43, wherein *Cu is ６７ The method is Cu.

69. 10. A method of treating cancer in a patient in need thereof, comprising administering to said patient an effective amount of the composition of any one of claims 1 to 21 and 23 to 43, wherein *Cu is ６７ The method is Cu.

70. 68. The method of claim 66 or 67, wherein the cancer is selected from somatostatin receptor-expressing tumors such as neuroendocrine tumors, prostate cancer and malignant meningiomas; FAP-overexpressing epithelial cancers and their respective microenvironments, including non-small cell lung cancer, triple-negative breast cancer, colorectal cancer, gastric cancer, ovarian cancer and pancreatic cancer.

71. 68. The method of 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 carcinoma, laryngeal cancer, myeloma cells, bladder cancer, cholangiocarcinoma, clear cell renal carcinoma, neuroendocrine tumors, oncogenetic osteomalacia, sarcoma, CUP (cancer of unknown primary), thymic carcinoma, desmoid tumor, glioma, astrocytoma, cervical cancer, and prostate cancer.

72. A method for producing a composition according to any one of claims 1 to 43.

73. A radiopharmaceutical composition comprising a radioactive moiety according to any one of claims 1 to 43.

74. 74. The radiopharmaceutical composition of claim 73, wherein said radiopharmaceutical composition comprises a means for generating an image according to claims 44 to 48 and 66, a means for detecting a disease according to claims 49 to 57, a means for monitoring cancer therapy according to claims 58 to 65 and 67, or a means for treating cancer according to claims 68 to 71.

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