Conjugates for cancer treatment and imaging

Abstract

The present invention relates to 47 Sc, 111 In, 161 The present invention relates to conjugates comprising a PSMA targeting compound bound to a radionuclide, such as Tb. These compounds, and pharmaceutical compositions comprising the compounds, can be used in medical applications including cancer treatment, as well as monitoring and diagnosis.

Description

[Technical field]

[0001] The present invention relates to 111 In, 161 Tb, 47 Sc, 68 Ga, 44 The present invention relates to conjugates that contain PSMA targeting compounds that bind to radionuclides such as Sc. These compounds, and pharmaceutical compositions that contain the compounds, can be used in medical applications including cancer treatment, as well as monitoring and diagnosis. [Background technology]

[0002] Prostate cancer is one of the most common causes of cancer-related deaths in men. There is a great demand for new and effective treatments, especially in hormone-refractory late-stage disease. Because bone metastases are often problematic in late-stage disease, alpha particle emitters have been proposed as bone-specific therapies for late-stage prostate cancer patients with bone metastases. 223 Ra (Xofigo) was introduced.

[0003] 223 Although Ra, as a bone-seeker, shows great clinical benefit to patients, its activity is restricted to bone metastases and does not target soft tissue metastases.

[0004] There are several carrier molecules for radioligand targeting of prostate-specific membrane antigen (PSMA). 177 Lu-PSMA-617) is the compound furthest along in clinical development for use in radionuclide therapy.

[0005] This molecule is 177 Lu and 225 For longer-lived (i.e., half-lives of several days) radionuclides, including Ac, it behaves in a suitable manner and produces suitable tumor-to-normal tissue ratios, but at early time points (typically several hours after injection), it shows high kidney uptake. 212For shorter-lived radionuclides such as Pb (half-life of 10.6 h), early renal uptake represents a potential toxicity problem.

[0006] Therefore, it is advantageous to use a PSMA ligand with low kidney uptake, but this should not impair tumor uptake. Alternatively, a PSMA-targeted radioligand with high initial kidney uptake can be combined with a radionuclide with a longer half-life if its retention in the tumor is much higher than its retention in the kidney. Also, molecules with high retention in both the tumor and kidney at early time points can be used for diagnostic scanning, e.g., PET and SPECT, to visualize tumor distribution, PSMA expression, etc. The PSMA ligand molecule consists of (1) a PSMA binding region, (2) a linker region, and (3) a chelator, whereby the linker region connects (1) and (3). The linker region is also used to adjust the molecular size, polarity, etc., and to affect the in vivo distribution characteristics. The PSMA binding region (motif) used for PSMA-617 is the same as that of PSMA-11, PSMA I&T, and 131 I and 211 This structure is found in several molecules of this class developed by several different inventors and researchers, such as the At-labeled PSMA-binding ligand.

[0007] Novel compounds containing the PSMA domain are needed because all ligands currently in testing suffer from challenges including relatively low relative radiobiological effectiveness (RBE) and suboptimal biodistribution.

[0008] There is also a need for improved alpha-emitters, beta-emitters, Auger-emitters, positron-emitters, and / or photon-emitters that can target both bone and soft tissue metastases, as well as compounds that can be used for imaging and diagnosis.

[0009] The present invention relates to compounds and compositions that address these problems. Summary of the Invention

[0010] The object of the present invention is to provide a compound of formula:

[0011] [ka] and b) 227 Th, 177 Lu, 212 Pb, 111 In, 203 Pb, 86 Y, 90 Y, 86 Y, 89 Zr, 68 Ga, 64 Cu, 67 Cu, 177 Lu, 225 Ac, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 48 Sc, 155 Tb, 149 Tb, and 161 a radionuclide selected from the group consisting of Tb and The present invention relates to a complex comprising:

[0012] One or more embodiments of the present invention provide a method for treating a radionuclide comprising the steps of: 111 In, 203 Pb, 86 Y, 90 Y, 86 Y, 89 Zr, 68 Ga, 64 Cu, 67 Cu, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 48 Sc, 155 Tb, 149 Tb, and 161 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is selected from the group consisting of: Tb. 111 In, 203 Pb, 86 Y, 90 Y,86 Y, 89 Zr, 68 Ga, 64 Cu, 67 Cu, 177 Lu, 225 Ac, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 48 Sc, 155 Tb, 149 Tb, and 161 The complex of the present invention is selected from the group consisting of Tb.

[0013] One or more embodiments of the present invention provide a method for treating a cancer cell comprising administering to a patient a radioactive nuclides comprising administering to said ... 177 One or more embodiments of the present invention relate to a complex of the invention in which the radionuclide is 225 One or more embodiments of the present invention relate to a conjugate of the present invention, wherein the radionuclide is 111 In one or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is In. 86 One or more embodiments of the present invention relate to a conjugate of the present invention, wherein the radionuclide is 90 One or more embodiments of the present invention relate to a conjugate of the present invention, wherein the radionuclide is 89 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Zr. 68 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Ga. 64 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Cu. 161 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Tb. 67 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Cu. 44 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Sc. 46 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Sc. 47One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Sc. 48 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Sc. 155 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Tb. 149 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Tb. 203 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is 43 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Sc. 161 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Tb. 177 One or more embodiments of the present invention relate to a complex of the invention in which the radionuclide is 227 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is 212 Pb.

[0014] One or more embodiments of the present invention relate to a conjugate or pharmaceutical composition of the present invention for use in imaging.

[0015] One or more embodiments of the present invention relate to a conjugate or pharmaceutical composition of the present invention for use in positron emission tomography (PET) imaging or single photon emission computed tomography (SPECT) imaging.

[0016] One or more embodiments of the present invention relate to the use of the conjugate or pharmaceutical composition of the present invention, wherein the imaging is for providing diagnosis, staging, and / or monitoring of treatment of cancer.

[0017] One or more embodiments of the present invention relate to methods of treating a malignant or non-malignant disease by administering a pharmaceutical composition of the present invention to an individual in need of such treatment.

[0018] One or more embodiments of the present invention relate to methods of ameliorating a malignant or non-malignant disease by administering a pharmaceutical composition of the present invention to an individual in need thereof.

[0019] One or more embodiments of the present invention relate to methods of inhibiting malignant or non-malignant disease by administering a pharmaceutical composition of the present invention to an individual in need thereof.

[0020] One or more embodiments of the present invention relate to a kit comprising a first vial containing a pharmaceutical composition of the present invention and a second vial containing a neutralizing composition for adjusting the pH and / or isotonicity of the radiopharmaceutical composition prior to administration to a patient.

[0021] One or more embodiments of the present invention include 111 In, 203 Pb, 86 Y, 90 Y, 86 Y, 89 Zr, 68 Ga, 64 Cu, 67 Cu, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 48 Sc, 155 Tb, 149 Tb, and 161 The kit comprises a first vial containing a pharmaceutical composition comprising Tb and a second vial containing p-SCN-Bn-DOTA-PSMA. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] Some abbreviations used Peptide mimetics, also called peptidomimetics, are small protein-like chains designed to mimic peptides. They are typically produced from the modification of existing peptides or by engineering similar systems that mimic peptides, such as peptoids or beta-peptides. Whatever the method, the altered chemical structure is designed to favorably tune molecular properties such as stability and biological activity. This may have a role in the development of drug-like compounds from existing peptides. Such modifications include changes to peptides that do not occur in nature, such as altering the backbone or incorporating unnatural amino acids. Based on their similarity to the precursor peptide, peptidomimetics can be divided into four classes (A-D), with A being characterized by the highest similarity and D being characterized by the lowest similarity. Classes A and B contain peptide-like backbones, while classes C and D contain small molecules.

[0023] PSMA - Prostate-specific membrane antigen. Synonyms PSMA, prostate-specific cancer antigen, PSM, FGCP, FOLH, GCP2, mGCP, GCPII, NAALAD1, NAALAdase, FOLH1, glutamate carboxypeptidase 2, glutamate carboxypeptidase II, membrane glutamate carboxypeptidase, N-acetylated alpha-linked acidic dipeptidase I, pteroylpolygammaglutamate carboxypeptidase, folylpolygammaglutamate carboxypeptidase, folate hydrolase 1, prostate-specific membrane antigen, cell proliferation inhibitory protein 27

[0024] p-SCN-Bn-DOTA-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid

[0025] DOTA-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid and benzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid are also used (eg, for conjugation with monoclonal antibodies).

[0026] The present invention is in the field of radiolabeled therapeutic and diagnostic agents that are PSMA peptidomimetics. According to the present invention, radiolabeled derivatives of urea-based prostate specific membrane antigen (PSMA) inhibitors are disclosed.

[0027] It is therefore an object of the present invention to provide a compound of formula:

[0028] [ka] and b) 227 Th, 177 Lu, 212 Pb, 111 In, 203 Pb, 86 Y, 90 Y, 86 Y, 89 Zr, 68 Ga, 64 Cu, 67 Cu, 177 Lu, 225 Ac, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 48 Sc, 155 Tb, 149 Tb, and 161 and a radioactive nuclide selected from the group consisting of Tb.

[0029] In addition, radionuclides are 111 In, 203 Pb, 86 Y, 90 Y, 86 Y, 89 Zr, 68 Ga, 64 Cu, 67 Cu,177 Lu, 225 Ac, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 48 Sc, 155 Tb, 149 Tb, and 161 Tb.

[0030] Therefore, p-SCN-Bn-DOTA-PSMA and 203 The Pb complex is referred to herein as 203 It is written as Pb-p-SCN-Bn-DOTA-PSMA.

[0031] Radionuclides One or more embodiments of the present invention provide a method for treating a radionuclide comprising the steps of: 227 Th, 177 Lu, 212 Pb, 111 In, 203 Pb, 86 Y, 90 Y, 86 Y, 89 Zr, 68 Ga, 64 Cu, 67 Cu, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 48 Sc, 155 Tb, 149 Tb, and 161 The complex of the present invention is selected from the group consisting of Tb.

[0032] In addition, radionuclides are 111 In, 203 Pb, 86 Y, 90 Y, 86 Y, 89 Zr, 68 Ga, 64 Cu, 67 Cu, 177 Lu, 225 Ac, 43 Sc, 44 Sc, 46Sc, 47 Sc, 48 Sc, 155 Tb, 149 Tb, and 161 The radionuclide may be selected from the group consisting of: Tb. 111 In, 203 Pb, 86 Y, 90 Y, 86 Y, 89 Zr, 68 Ga, 64 Cu, 67 Cu, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 48 Sc, 155 Tb, 149 Tb, and 161 One or more embodiments of the present invention may comprise a radionuclide selected from the group consisting of Tb, 177 One or more embodiments of the present invention relate to a complex of the invention in which the radionuclide is 225 One or more embodiments of the present invention relate to a conjugate of the present invention, wherein the radionuclide is 111 In one or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is In. 86 One or more embodiments of the present invention relate to a conjugate of the present invention, wherein the radionuclide is 90 One or more embodiments of the present invention relate to a conjugate of the present invention, wherein the radionuclide is 89 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Zr. 68 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Ga. 64 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Cu. 161 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Tb. 67 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Cu. 44One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Sc. 46 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Sc. 47 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Sc. 48 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Sc. 155 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Tb. 149 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Tb. 203 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is 43 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Sc. 161 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is Tb. 177 One or more embodiments of the present invention relate to a complex of the invention in which the radionuclide is 227 One or more embodiments of the present invention relate to a complex of the present invention, wherein the radionuclide is 212 Pb.

[0033] Pharmaceutical Compositions The compounds or conjugates of the present disclosure are typically applied in the treatment or monitoring of a disease and are typically formulated into a pharmaceutical composition.

[0034] Such compositions are optimized for parameters such as physiological tolerance and shelf life.

[0035] One or more embodiments of the present disclosure relate to a pharmaceutical composition comprising a compound or conjugate of the present disclosure and a pharma- ceutically acceptable carrier and / or excipient.

[0036] One or more embodiments of the present disclosure relate to a pharmaceutical composition comprising a compound or conjugate of the present disclosure and a pharma- ceutically acceptable diluent, carrier, surfactant, and / or excipient.

[0037] Acceptable pharmaceutical carriers include, but are not limited to, non-toxic buffers, bulking agents, isotonic solutions, etc. More specifically, the pharmaceutical carrier can be, but is not limited to, saline (0.9%), half saline, lactated Ringer's solution, 5% dextrose, 3.3% dextrose / 0.3% saline.

[0038] Physiologically acceptable carriers may contain radiolytic stabilizers, such as ascorbic acid, which protect the integrity of the pharmaceutical agent during storage and transportation.

[0039] One or more embodiments of the present invention relate to pharmaceutical compositions of the present invention administered at a radioactivity of 100 kBq to 50 GBq per dose.

[0040] Imaging One or more embodiments of the present invention relate to the use of the complex or pharmaceutical composition of the present invention, wherein the imaging is for providing a diagnosis, stage, and / or treatment monitoring of cancer. The imaging can be for providing a diagnosis of cancer. The imaging can be for providing a stage of cancer. The imaging can be for providing a treatment monitoring of cancer.

[0041] One aspect of the disclosure relates to compounds, conjugates, and pharmaceutical compositions according to the disclosure, wherein the radionuclide is suitable for imaging, i.e., e.g. 227 Th, 177 Lu, 212 Pb, 111 In, 203 Pb, 86 Y, 90 Y, 86 Y, 89 Zr, 68 Ga, 64 Cu, 67 Cu, 43 Sc,44 Sc, 46 Sc, 47 Sc, 48 Sc, 155 Tb, 149 Tb, 161 Tb, and 11 C. 13 N, 15 O. 18 F. Also, the radionuclide may be selected from the group consisting of: 111 In, 203 Pb, 86 Y, 90 Y, 86 Y, 89 Zr, 68 Ga, 64 Cu, 67 Cu, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 48 Sc, 155 Tb, 149 Tb, 161 Tb, and 11 C. 13 N, 15 O. 18 It may be selected from the group consisting of F.

[0042] One or more embodiments of the present invention relate to a conjugate or pharmaceutical composition of the present invention for use in positron emission tomography (PET) imaging.One or more embodiments of the present invention relate to a conjugate or pharmaceutical composition of the present invention for use in single photon emission computed tomography (SPECT) imaging.

[0043] Positron Emission Tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes and other physiological activities such as blood flow, local chemical composition, and absorption. Different tracers are used for various imaging purposes depending on the target process in the body. PET is a medical scintigraphy technique, which is a common imaging technique used in nuclear medicine. Radiopharmaceuticals (radioactive nuclides bound to drugs) are injected into the body as tracers. The tracers of the present invention are the complexes and pharmaceutical compositions of the present invention, where p-SCN-Bn-DOTA-PSMA is a compound or drug, and the complex is a radiopharmaceutical.

[0044] Gamma rays are emitted and detected by a gamma camera to form a three-dimensional image, similar to how an X-ray image is taken. A PET scanner can incorporate a CT scanner, known as a PET-CT scanner. A PET scan image can be reconstructed using a CT scan performed using a single scanner during the same session. Thus, in one or more embodiments of the present invention, the complex and pharmaceutical composition of the present invention are used in PET or PET-CT imaging.

[0045] Single photon emission computed tomography (SPECT, or less commonly SPET) is a nuclear medicine tomographic imaging technique that uses gamma radiation. It is very similar to conventional nuclear medicine planar imaging (i.e. scintigraphy) that uses a gamma camera, but can provide true 3D information. This information is typically presented as cross-sectional slices of the patient, but can be freely reformatted or manipulated as needed. This technique requires the delivery of gamma-emitting radioisotopes (radionuclides of the present invention) to the patient, usually through injection into the bloodstream. In most cases, however, marker radionuclides are bound to specific ligands to create radioligands that bind to specific types of tissues due to their properties. This binding transports and binds the ligand-radiopharmaceutical combination to the desired location in the body, where the ligand concentration is confirmed by a gamma camera. The radioligand of the present invention is the conjugate described above. Thus, in one or more embodiments of the present invention, the conjugates and pharmaceutical compositions of the present invention are used in SPECT imaging.

[0046] In one embodiment, the imaging is to provide cancer diagnosis, staging, and treatment monitoring.

[0047] In one embodiment, the imaging is to provide monitoring of the cancer, without the involvement of a physician, and essentially data obtained from the imaging procedure, which allows monitoring changes, such as progression or regression, of the cancer over time.

[0048] Accordingly, one or more embodiments of the present disclosure relate to compounds, conjugates, and pharmaceutical compositions according to the present disclosure for use in imaging.

[0049] Position-emitting compounds, conjugates, and pharmaceutical compositions according to the present disclosure are typically prepared immediately prior to imaging due to the relatively short half-life of the positron-emitting nuclides.

[0050] The compounds, conjugates, and pharmaceutical compositions according to the present disclosure typically comprise a targeting molecule bound to a compound enriched with a positron-emitting isotope.

[0051] Additionally, the compounds, conjugates, and pharmaceutical compositions according to the present disclosure include 11 C. 13 N, 15 O or 18 F may be enriched.

[0052] kit In the case of a kit, the composition of the invention should be made physiologically suitable for injection either at a centralized production site or configured in a kit system, typically consisting of 2-4 vials, whereby the vials of the kit should be made physiologically suitable for injection after combining them.

[0053] Thus, one aspect of the present invention relates to a kit comprising a first vial containing a pharmaceutical composition according to the present invention and a second vial containing a neutralization solution for adjusting the pH and / or isotonicity of the radiopharmaceutical composition prior to administration to a patient.

[0054] For example, in the case of monoclonal antibodies, it is usually desirable to keep the self-dosage of alpha particle-producing radiopharmaceutical solutions below 0.5 kGy to avoid loss of binding properties due to radiolysis. Therefore, depending on the radiolysis resistance of the radioligand produced, for concentrated solutions intended for long-distance transport, a kit system in which the compound of the invention is added to a composition containing a radionuclide several hours to 10 minutes before injection is advisable.

[0055] One or more embodiments of the present invention relate to a kit comprising a first vial containing a pharmaceutical composition of the present invention and a second vial containing a neutralizing composition for adjusting the pH and / or isotonicity of the radiopharmaceutical composition prior to administration to a patient.

[0056] One or more embodiments of the present invention include 227 Th, 177 Lu, 212 Pb,111 In, 203 Pb, 86 Y, 90 Y, 86 Y, 89 Zr, 68 Ga, 64 Cu, 67 Cu, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 48 Sc, 155 Tb, 149 Tb, and 161 The present invention relates to a kit comprising a first vial containing a pharmaceutical composition comprising Tb and a second vial containing p-SCN-Bn-DOTA-PSMA. 111 In, 203 Pb, 86 Y, 90 Y, 86 Y, 89 Zr, 68 Ga, 64 Cu, 67 Cu, 43 Sc, 44 Sc, 46 Sc, 47 Sc, 48 Sc, 155 Tb, 149 Tb, and 161 Tb.

[0057] The kit can optionally include instructions for use.

[0058] Medical Use One aspect of the invention relates to a pharmaceutical composition according to the invention for use as a medicament.

[0059] In one embodiment of the invention, the disease is cancer.

[0060] One aspect of the invention relates to a pharmaceutical composition according to the invention for use in the treatment of soft tissue and / or bone diseases. The treatment focuses on PSMA-expressing diseases, such as soft tissue diseases and bone diseases.

[0061] One embodiment of the present invention is a bone disease selected from the group consisting of soft tissue and / or bone metastases from breast cancer, prostate cancer, kidney cancer, lung cancer, bone cancer, or multiple myeloma.

[0062] In one embodiment of the invention, the cancer is prostate cancer. The cancer can be breast cancer. The cancer can be kidney cancer. The cancer can be lung cancer. The cancer can be bone cancer. The cancer can be multiple myeloma. The cancer can be a metastasis from these types of cancer.

[0063] Thus, the complexes and solutions of the present invention can be used in the treatment of metastatic prostate cancer.

[0064] In one embodiment of the invention, the solution is administered at a dose in the range of 50 kBq to 500 MBq per kg of body weight, for example 50 kBq to 100 MBq per kg of body weight.

[0065] One aspect of the present invention relates to a method of treating a malignant or non-malignant disease by administering a pharmaceutical composition according to the present invention to an individual in need of such treatment.

[0066] Another aspect of the present invention relates to a method of ameliorating a malignant or non-malignant disease by administering to an individual in need thereof a pharmaceutical composition according to the present invention.

[0067] Yet another aspect of the present invention relates to a method of inhibiting a malignant or non-malignant disease by administering a pharmaceutical composition according to the present invention to an individual in need thereof.

[0068] Preparation method One aspect of the present invention relates to a method for providing a pharmaceutical composition according to the present invention, the method comprising the steps of providing a first composition comprising a radionuclide, providing a second composition comprising a complexing agent (i.e., p-SCN-Bn-DOTA-PSMA), where the complexing agent is capable of complexing the radionuclide, and mixing the first and second compositions, thereby providing a pharmaceutical composition according to the present invention.

[0069] Activity Level When the complexes of the invention are used alone, the activity level will typically be between 1MBq and 50GBq per patient, more typically 10MBq to 20GBq per patient. For alpha emitters, the level is typically at the lower end of the interval, and for beta emitters, the level is typically at the upper end of the interval. Also of note is that administration can be given as a single dose or as repeated doses, typically 2 to 10. Thus, for alpha emitters, the dose range is typically 5MBq to 500MBq, and for beta emitters, the dose range is typically 1GBq to 50GBq. For diagnostic applications, the dose range is typically 100MBq to 10GBq.

[0070] Additionally, doses can be between 0.1 MBq and 50 GBq per patient, more typically between 1 MBq and 20 GBq per patient.

[0071] The following figures and examples are provided below to illustrate the present invention, which are intended for illustrative purposes and are not to be construed as limiting in any sense. EXAMPLES

[0072] Example 1 68 Radiolabeling of p-SCN-Bn-DOTA-PSMA with Ga 10 nmol of p-SCN-Bn-DOTA-PSMA was preheated at 90 °C for 5 min, and then 280 μl of the stock solution was added. 68Ga, and 5 μl of NH4OAc (=50 μg / ml) were added. The pH was adjusted to about 5-6 with 5 M NH4OAc. The activity of the solution was measured in a Capintec dosimetry instrument. The solution was then incubated at 90°C and 650 rpm, and the RCP was measured after 15 min using an instant thin layer chromatography (model #150-772, Biodex Medical System Inc, Shirley, NY) and a Cobra gamma counter with a window between 50 and 2000 keV.

[0073] Radioligand binding at the antigen excess used was assessed by a one-point binding assay (RCP correction). The PSMA-expressing prostate cancer cell line C4-2 (ATCC CRL3314, Manassas, VA)38 was cultured in monolayer in RPMI 1640 medium (Sigma-Aldrich Norway AS, Oslo, Norway) supplemented with 10% heat-inactivated fetal bovine serum (FBS, GE Healthcare Life Sciences, Chicago, IL), 100 units / mL penicillin, and 100 μg / mL streptomycin (Sigma-Aldrich) at 37 °C in a humidified atmosphere of 95% air and 5% CO2. Cell binding of the radiolabeled ligand was verified by a similar cell binding assay. In this assay, 10–12 × 10 6 Cells were incubated with 1.5–6 nM radioligand. The cell-bound fraction (% of added cell-bound activity) was estimated by subtracting the nonspecific cell-binding activity from the total cell-binding activity.

[0074] The results are shown in Table 1.

[0075] This example demonstrates that p-SCN-Bn-DOTA-PSMA can be synthesized with adequate yield and good cell binding capacity of the radioligand. 68 It shows that it can be labeled with Ga.

[0076] [Table 1]

[0077] Example 2 203 Lead-212 labeling of p-SCN-Bn-DOTA-PSMA as an indicator for preparing Pb-labeled p-SCN-Bn-DOTA-PSMA 25 nmol of p-SCN-Bn-DOTA-PSMA was preheated at 37 °C for 5 min, and then 100 μl of the stock solution (0.1 M HCL) prepared as described (Li RG et al., 2023) was added. 212 Pb and 10 μl of 5 M NH4OAc were added. The pH was adjusted to about 5-6 with 5 M NH4OAc. The activity of the solution was measured in a Capintec dosimeter. The solution was then incubated at 37°C and 650 rpm (Thermomixer Comfort, Eppendorf, Germany) and the RCP was measured after 15 min using instant thin layer chromatography (ITLC) (model #150-772, Biodex Medical System Inc, Shirley, NY) and a Cobra gamma counter with a window between 50 and 2000 keV.

[0078] Radioligand binding at antigen excess was assessed using a single-point binding assay with PSMA-expressing C4-2 cell line (ATCC CRL3314, Manassas, VA) grown in monolayer at 37 °C in a humidified atmosphere of 95% air and 5% CO2 in RPMI 1640 medium (Sigma-Aldrich Norway AS, Oslo, Norway) supplemented with 10% heat-inactivated fetal bovine serum (FBS, GE Healthcare Life Sciences, Chicago, IL), 100 units / mL penicillin, and 100 μg / mL streptomycin (Sigma-Aldrich). Cell binding of the radiolabeled ligand was verified by a cell binding assay. In this assay, 10–12 × 10 6 The cells were incubated with 1.5-6 nM of radioligand.

[0079] Nonspecific binding was measured in cells preincubated with an excess of unlabeled ligand before the addition of radioligand. The cell-bound fraction (% of added activity) was estimated by subtracting the nonspecific cell-bound activity from the total cell-bound activity.

[0080] Results: The radiochemical purity of the radiolabeled products from the two batches was determined to be 94.5-98.7% by ITLC. The cell-associated fraction was found to be 47.3-55.0%.

[0081] Conclusion: 212 Pb, 203 When used as an indicator for Pb labeling, the data demonstrated high and adequate labeling yields, as well as adequate cell binding capacity of the radioligand.

[0082] Example 3: To mimic the radioligand of 203Pb-p-SCN-Bn-DOTA-PSMA 212 Biodistribution of Pb-labeled p-SCN-Bn-DOTA-PSMA For biodistribution studies, male Hsd:Athymic Nude-Foxn1nu mice maintained at the Department of Comparative Medicine, Norwegian Radium Hospital (Oslo University Hospital, Oslo, Norway) were used.

[0083] Mice were inoculated on both flanks with 10 × 10 6 C4-2 cells were inoculated subcutaneously in a total volume of 200 uL. Tumors were grown in volumes ranging from 300 to 1500 mm for biodistribution studies. 3 Tumors were allowed to grow until they reached 100 μg / ml and tumor-bearing mice were randomized based on tumor size prior to injection of the radioligand.

[0084] The study was approved by the Institutional Committee on Research Animal Care (Department of Comparative Medicine, Oslo University Hospital) and the Norwegian Food Safety Authority (Brümundsdal, Norway). All procedures and experiments with animals in this study were performed in accordance with the Interdisciplinary Principles and Guidelines for the Use of Animals in Research, Marketing and Education (New York Academy of Sciences, New York, USA) and EU Directive 2010 / 63 / EU, as well as the ARRIVE guidelines. Animals were kept in a specific pathogen-free environment and had free access to food and water. Cages (1–5 per cage) were housed in a Scantainer where temperature (24°C) and humidity (60%) were kept constant. Mice were 4–6 weeks old and weighed 25–35 g at the start of the study. Mice (N=3 per time point) were injected intravenously with 86 kBq of 100 μg of 100 μg of isotonic saline solution at 24°C for 1 h. 212 Pb-p-SCN-Bn-DOTA-PSMA was injected and animals were sacrificed by cervical dislocation at 1 and 4 hours post-injection. The percentage of injected activity per gram of tissue was calculated by measuring the weight of the tissue sample and the radioactivity in the tissue sample, and the % injected activity per gram of tumor was divided by the % injected activity per gram of tissue to determine the tumor-to-tissue ratio.

[0085] Results: Tumor to muscle and tumor to bone ratios are presented in Table 2. The data show very good uptake ratios between tumor and muscle and between tumor and bone, and are consistent with the use of lead radioisotopes as radioligands, e.g. 203 Pb-labeled p-SCN-Bn-DOTA-PSMA has been shown to have promising properties for use in diagnostic nuclear medicine imaging, for example using gamma camera scanning.

[0086] [Table 2]

[0087] Conclusion: p-SCN-Bn-DOTA-PSMA is a promising molecule for use in diagnostic imaging of patients with PSMA-expressing tumors, e.g., as a radioligand imaging with single-photon emission computed tomography (SPECT) and / or positron emission tomography (PET) radionuclides.

[0088] reference Ruth Gong Li, Vilde Yuli Stenberg, and Roy Hartvig Larsen.An Experimental Generator for Production of High-Purity 212Pb for Use in Radiopharmaceuticals.Journal of Nuclear Medicine January 2023, 64(1)173~176;

Claims

1. a) Formula: 【Chemistry 1】 and a compound according to b) ４３ Sc, ４４ Sc, ４６ Sc, ４７ Sc, ４８ Sc, ６４ Cu, ６７ Cu, １１１ In, ８６ Y. ９０ Y. ８９ Zr, ２０３ Pb, １４９ Tb, １５５ Tb, and １６１ and a radionuclide selected from Tb.

2. The radionuclide ４３ Sc, ４４ Sc, ４６ Sc, ４７ Sc, or ４８ Sc. The complex of claim 1.

3. The radionuclide ６４ Cu or ６７ 2. The composite of claim 1, wherein the metal is Cu.

4. The radionuclide １１１ 2. The complex of claim 1, wherein In is In.

5. The radionuclide ８６ Y or ９０ Y. The conjugate of claim 1 .

6. The radionuclide ８９ 2. The composite of claim 1, wherein Zr is

7. The radionuclide ２０３ 2. The composite of claim 1, wherein the metal is Pb.

8. The radionuclide １４９ Tb, １５５ Tb, or １６１ The complex of claim 1, wherein the complex is Tb.

9. A pharmaceutical composition comprising the conjugate of any one of claims 1 to 8 and a diluent, carrier, surfactant, and / or excipient.

10. 10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is administered at a radioactivity of 100 kBq to 50 GBq per dose.

11. a method of treating the human or animal body by therapy, or a diagnostic method carried out on said human or animal body The pharmaceutical composition according to claim 9 for use in

12. 10. The pharmaceutical composition of claim 9 for use in treating PSMA-expressing diseases, including soft tissue diseases and bone diseases.

13. 10. The pharmaceutical composition of claim 9 for use in treating a disease selected from breast cancer, prostate cancer, kidney cancer, lung cancer, bone cancer, or bone metastasis from multiple myeloma.

14. 10. The pharmaceutical composition of claim 9 for use in cancer imaging.

15. 10. The pharmaceutical composition of claim 9 for use in positron emission tomography (PET) imaging or single photon emission computed tomography (SPECT) imaging.

Images