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US-12622984-B2 - High purity copper radiopharmaceutical compositions and diagnostic and therapeutic uses thereof

US12622984B2US 12622984 B2US12622984 B2US 12622984B2US-12622984-B2

Abstract

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

Inventors

  • Leila JAAFAR-THIEL
  • Melpomeni Fani
  • Jacopo Millul
  • Francesco De Rose

Assignees

  • NUCLIDIUM AG
  • UNIVERSITY OF BASEL

Dates

Publication Date
20260512
Application Date
20230928

Claims (20)

  1. 1 . A pharmaceutical composition comprising a compound and a pharmaceutically acceptable excipient, wherein the compound is of Formula 30: or is a pharmaceutically acceptable salt thereof; wherein: R 1 is R a ; R 2 and R 3 are each R a or together form a C 2-9 heterocycle with the nitrogen atoms to which they are attached; R a , independently for each occurrence, is selected from H, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 2-9 heterocyclyl, or C 5-9 heteroaryl, wherein each 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 is optionally substituted by one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH 2 , —NHR′, —N(R′) 2 , —NHCOR′, —NR′COR′, halogen, —CN, —CO 2 H, —CO 2 R′, —CHO, —COR′, —CONH 2 , —CONHR′, —CON(R′) 2 , —NO 2 , —OP(O)(OH) 2 , —SO 3 H, —SO 3 R′, —SOR′, and —SO 2 R′, wherein R′, independently for each occurrence, is C 1-10 alkyl or C 3-10 cycloalkyl; n is an integer from 1 to 20; m is an integer from 1 to 20; and *Cu is 61 Cu obtained by deuteron irradiation of nat Ni or 60 Ni on a niobium backing or by proton irradiation of 61 Ni on a niobium backing; and wherein (a) the composition is characterized at end of synthesis by radiochemical purity of ≥95%; (b) the composition is characterized at end of synthesis by radionuclidic purity for 61 Cu of ≥99.999%; (c) the 61 Cu is characterized at end of synthesis by sum of radionuclidic impurities of ≤6000 Bq/g; (d) the 61 Cu is characterized at end of synthesis +12 hours by radionuclidic purity of ≥99.985%; or (e) the 61 Cu is characterized at end of synthesis by 56 Co activity concentration of ≤800 Bq/g and 58 Co activity concentration of ≤800 Bq/g.
  2. 2 . The composition of claim 1 , wherein R 1 is methyl or H.
  3. 3 . The composition of claim 1 , wherein R 2 is H and R 3 is H.
  4. 4 . The composition of claim 1 , wherein R 2 and R 3 together form a C 2-9 heterocycle with the nitrogen atoms to which they are attached.
  5. 5 . The composition of claim 4 , wherein the C 2-9 heterocycle is a 6-membered heterocycle selected from a piperazine, hexahydropyrimidine, hexahydropyridazine, 1,2,3-triazinane, 1,2,4-triazinane, and 1,3,5-triazinane.
  6. 6 . The composition of claim 1 , wherein the compound of Formula 30 is of Formula 30a or Formula 30b:
  7. 7 . The composition of claim 6 , wherein R 1 is H or methyl.
  8. 8 . The composition of claim 1 , wherein the compound is selected from: Compound Structure *Cu-NODAGA-F1 *Cu-NODAGA-F2 *Cu-NODAGA-F3 *Cu-NODAGA-F4 or is a pharmaceutically acceptable salt thereof.
  9. 9 . The composition of claim 1 , wherein the composition is characterized at end of synthesis by radiochemical purity of ≥97%.
  10. 10 . The composition of claim 1 , wherein the composition is characterized at end of synthesis by radiochemical purity of ≥98%.
  11. 11 . The composition of claim 1 , wherein the composition is characterized at end of synthesis by radiochemical purity of ≥99%.
  12. 12 . The composition of claim 1 , wherein the composition has a pH from 4 to 7.
  13. 13 . A method of generating one or more images of a subject comprising: administering to the subject an effective amount of the composition of claim 1 ; and generating one or more images of at least a part of the subject's body.
  14. 14 . The method of claim 13 , wherein the one or more images are generated using positron emission tomography (PET), PET-computer tomography (PET-CT), or single-photon emission computerized tomography (SPECT).
  15. 15 . The method of claim 14 , wherein the one or more images are generated using PET-CT.
  16. 16 . A theranostic method comprising: (a) administering to a subject an effective amount of a first pharmaceutical composition, wherein the composition is according to claim 1 ; (b) generating one or more images of at least a part of the subject's body; and (c) administering to the subject an effective amount of a second pharmaceutical composition comprising a compound, wherein the compound is of Formula 30: or is a pharmaceutically acceptable salt thereof; wherein: R 1 is R a ; R 2 and R 3 are each R a or together form a C 2-9 heterocycle with the nitrogen atoms to which they are attached; R a , independently for each occurrence, is selected from H, C 1-10 alkyl, C 2-10 alkenyl, C 3-10 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 2-9 heterocyclyl, or C 5-9 heteroaryl, wherein each 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 is optionally substituted by one or more substituents selected from —OH, —OR′, ═O, ═S, —SH, —SR′, —NH 2 , —NHR′, —N(R′) 2 , —NHCOR′, —NR′COR′, halogen, —CN, —CO 2 H, —CO 2 R′, —CHO, —COR′, —CONH 2 , —CONHR′, —CON(R′) 2 , —NO 2 , —OP(O)(OH) 2 , —SO 3 H, —SO 3 R′, —SOR′, and —SO 2 R′, wherein R′, independently for each occurrence, is C 1-10 alkyl or C 3-10 cycloalkyl; n is an integer from 1 to 20; m is an integer from 1 to 20; and *Cu is 67 Cu.
  17. 17 . The method of claim 16 , wherein: 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; 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; 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 the compound of the first pharmaceutical composition is [ 61 Cu]Cu-NODAGA-F4 and the compound of the second pharmaceutical composition is [ 67 Cu]Cu-NODAGA-F4.
  18. 18 . The method of claim 16 , further comprising determining, via the one or more images of the subject, the presence or absence of a disease in the subject based on the presence or absence of localization of the 61 Cu radionuclide of the first pharmaceutical composition in the subject's body.
  19. 19 . The method of claim 18 , wherein the disease is selected from cancers, inflammatory diseases, infectious diseases, and immune diseases.
  20. 20 . The method of claim 16 , wherein the one or more images are generated by using positron emission tomography (PET), PET-computer tomography (PET-CT), or single-photon emission computerized tomography (SPECT).

Description

1. BACKGROUND The present disclosure is directed to a new class of radiotracers with potential for “true theranostic” use combining cancer diagnostics and therapy with a single chemical entity that meets the requirements of an ideal Positron Emission Tomography (PET) or single-photon emission computerized tomography (SPECT) tracer, based on a novel high purity 6xCu radionuclide production platform. More specifically, the present disclosure relates to novel constructs and compositions thereof and their use in imaging, diagnosing, and treatment of conditions such as myocardial infarct, interstitial lung disease, and cancer, including prostate cancer, epithelial tumors expressing FAP, and neuroendocrine tumor, as well as to methods of making these compositions. In nuclear medicine, radiotracers are used for the diagnosis and therapy of various conditions and diseases. Radiotracers are compounds in which radionuclides are linked to targeting moieties that target specific organs, cells, or biomarkers in the human body. Radiotracers can be used in targeted radionuclide therapy with the use of targeting moieties that selectively localize in malignant cells, tumors, or the microenvironments associated therewith, and with radionuclides selected to emit low-range highly ionizing radiation, e.g., α or β− particles. The combination of both the diagnosis and the treatment of a disease utilizing the same or similar biological targeting moieties which target a specific biomarker (e.g., a cell surface receptor) with different diagnostic and therapeutic radionuclides is called targeted theranostics. This approach overcomes the difficulty of quantifying the individual dose needed for the therapy through the diagnosis, rendering the treatment of the patient highly individualized. The theranostic approach is further improved using radionuclides of the same element, e.g., copper radionuclides, 60Cu, 61Cu, 62Cu, and 64Cu as positron emitters in diagnostic imaging and 67Cu as an electron-emitter in the radiotherapeutic, as the isotopically different radiotracers will bind identically to the biomarker. The availability of a large portfolio of active and highly pure radiotracers is essential for the development of nuclear medicine. A variety of copper radionuclides have been used in the field of nuclear medicine, and they offer versatile choices for applications in radionuclide imaging (e.g., in radiotracers) and therapy. Copper radionuclides, including 60Cu, 61Cu, 62Cu, 64Cu, and 67Cu, offer versatile choices for applications in imaging and therapy. The short-lived 60Cu (t1/2=23.4 min), 61Cu (t1/2 3.32 h) and 62Cu (t1/2=9.76 min) decay by electron capture and β+ emission, and they have been used as to prepare perfusion agents such as Cu-pyruvaldehyde bis(N4-methylthiosemicarbazone) (PTSM) and Cu-ethylglyoxal bis(thiosemicarbazone) ETS. The longer-lived 67Cu (t1/2=62.01 h) decays exclusively by β− emission and has been used to label monoclonal antibodies and antibody fragments for radioimmunotherapy. 64Cu has an intermediate half-life of 12.7 h and unique decay prolife (β+: 18%, β−: 38%, and electron capture: 44%), making it useful for radiolabeling nanoparticles, antibodies, antibody fragments, peptides, and small molecules for PET imaging and radionuclide therapy. 64Cu radiopharmaceuticals can thus be used for quantitative PET imaging to calculate radiation dosimetry prior to performing targeted radiotherapy with 64Cu or its beta-emitting isotopologue 67Cu. 64Cu has been incorporated into many labelled radiotracers based on antibodies, peptides and small molecules that target specific receptors or antigens, particularly in oncology applications. More recently, 61Cu (t1/2=3.33 h, 61% β Emax=1.216 MeV) has been considered a better choice for prolonged imaging of processes with slower kinetics due to its longer half-life (3.33 h) than that of 60Cu and 62Cu. 61Cu is a positron-emitting radionuclide presenting decay characteristics comparable to [68Ga]Ga but with the advantage of presenting lower maximum positron energy (Emax=1.216 MeV vs. Emax=1.899 MeV) and a substantially more practical half-life (3.33 h vs. 68 min). (McCarthy, D. W. et al. High purity production and potential applications of copper-60 and copper-61. Nucl. Med. Biol. 1999, 26, 351-358.) The intermediate half-life and interesting decay properties allow for better image quality and possibly lower radiation dose to patients. Radionuclides can be used in personalized medicine but their supply in quantity and quality for clinical applications represents a challenge. Production of target “coins” (the often disk-like objects bearing a target metal that is bombarded with subatomic particles in order to produce radionuclides) that can produce radionuclide compositions having activity, at end of bombardment (EoB), end of synthesis (EoB+2 hours), or at calibration, with the required radionuclide purity is crucial. Suitable target coin preparation is one of the most important