PSMA-targeting ligands with optimal properties for imaging and therapy

Abstract

Disclosed herein are theranostic agents incorporating a chelating moiety capable of chelating a radioactive metal isotope and a PSMA targeting moiety. The theranostic agents that can be used to treat and / or detect cancers associated with increased PSMA expression have the formula and include complexes, anions, or salts thereof. R1 comprises a chelating moiety, a is 0 or 1, n is an integer between 12 and 21, and R2 comprises a prostate specific membrane antigen (PSMA) targeting moiety. Optionally, the chelating moiety is chelated to a metal atom, where the metal atom is a positron or single photon emitting metal isotope, or an alpha, beta, or Auger emitting metal isotope. [Formula 1] JPEG2024517657000047.jpg2071

Description

[Technical field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims priority to U.S. Provisional Application No. 63 / 178,566, filed April 23, 2021, which is incorporated by reference in its entirety.

[0002] [Statement regarding federally sponsored research or development] N / A

[0003] [Disclosure Areas] The present disclosure relates generally to disease treatment and medical diagnosis / imaging. In particular, the present disclosure relates to therapeutic agents that target prostate-specific membrane antigen (PSMA), which may optimally include chelated radioactive metal isotopes, for targeting and treating prostate cancer and detecting / imaging prostate cancer. [Background technology]

[0004] "Theranostics", a term derived from the combination of therapeutic and diagnostic methods, is an emerging medical field in which a medical condition can be diagnosed and treated simultaneously or sequentially using drugs that target a specific disease. Theranostics has become an important area of ​​research and development in medical physics, where changing the isotopes of radionuclides present in a specific disease targeting material can transform the disease targeting material from an imaging probe (e.g., by using β+ or γ-emitting isotopes to facilitate positron emission tomography (PET) or single-photon emission computed tomography (CT) imaging, respectively) to a therapeutic probe (e.g., by using α- or β-particle or Auger electron emitting isotopes to facilitate targeted radiotherapy).

[0005] Prostate-specific membrane antigen (PSMA) can be overexpressed in metastatic cancers (including, but not limited to, prostate cancer) compared to normal tissues, and radionuclide tracers specific for PSMA have been developed for PET imaging and targeted radiotherapy. For example, PSMA targeting moieties containing the Glu-Urea-Lys PSMA binding motif have been conjugated to various metal chelators (e.g., DOTA, NOTA) to generate ligands such as PSMA-11, PSMA-617, PSMA-R2, and PSMA I&T. These ligands can potentially be chelated with appropriate radionuclides for specific theranostic applications.

[0006] Although many such ligands targeting PSMA are known in the art, these ligands suffer from a number of significant drawbacks. Specifically, they exhibit relatively short blood circulation half-lives and poor tumor retention. In addition, they exhibit significant off-target binding and are differentially retained in both salivary gland and kidney tissues. Furthermore, these known ligands are excreted by the kidney (with little or no excretion from the liver) and are generally administered together with one or more albumin binders, resulting in less than ideal bioavailability. Thus, there is a need in the art for improved cancer-targeting theranostic agents for use in radiotherapy and / or imaging applications that do not suffer from these drawbacks.

[0007] An additional consideration for known PSMA targeting ligands is the suitability of the ligand for targeted radiotherapy using α or Auger electron emitters. The different types of particles emitted for radiotherapy (e.g. α or β-particles or Auger electrons) have different linear energy transfer (LET), which determines the effective dose per distance for each particle type. The higher the LET, the more radiation dose is deposited in a given area. Because alpha particles and Auger electrons have high LET, for effective treatment, ligands used to deliver radionuclides emitting such particles must deliver the radionuclide as close to the target as possible. However, known ligands are not optimized for this and are therefore unsuitable for targeted radiotherapy delivered by α or Auger electron emitters.

[0008] Thus, there is a further need in the art for improved cancer-targeted theranostic agents for use in radiation therapy that are optimized for use with alpha or Auger electron emitters.

[0009] [Brief Overview] The present disclosure provides new theranostic agents and radioactive metal chelates for cancer imaging and / or radiotherapy. A variety of positron and gamma emitting metals suitable for PET or SPECT imaging are available for chelation, as well as a variety of alpha, beta, and Auger emitting metal nuclides for targeted radiotherapy.

[0010] The theranostic agents disclosed herein utilize a PSMA targeting moiety in combination with one of a variety of metal chelating moieties that can be chelated to a radioactive metal isotope as needed. The pharmacokinetics and related properties of the theranostic agent can be tailored and optimized by altering the structure of the linker between the PSMA targeting moiety and the metal chelating moiety.

[0011] Specifically, to tune the pharmacokinetics of the theranostic agent, the length of the carbon chain of the linker was altered, thereby altering the hydrophobicity of the theranostic agent. The effect of altering the hydrophobicity of the theranostic agent on the pharmacokinetics was also investigated. Longer carbon chains increase hydrophobicity and increase circulating half-life. Overall, the disclosed theranostic agents exhibit longer circulating half-life, bioavailability, and fewer off-target targeting properties compared to known ligands. Additionally, the excretion pathway of the theranostic agent can be tuned, with increased hydrophobicity correlating with increased hepatic excretion (and decreased renal excretion). Finally, the disclosed theranostic agents can be optimized for specific use in targeted alpha therapy.

[0012] The disclosed theranostic agents preferentially bind to cancer cells with increased PSMA expression compared to normal cells. Thus, these agents can be used for the treatment of prostate cancer and other cancers associated with increased PSMA expression, as well as for cancer detection / imaging applications. In therapeutic treatments, the theranostic agents include chelated radioactive metal isotopes that deliver therapeutic amounts of radiation locally to cancer cells. In detection / imaging applications, the theranostic agents include chelated radioactive metal isotopes that are suitable for emitting signals that can be used for detection / imaging.

[0013] Thus, the present disclosure encompasses a family of theranostic agents that can be used as cancer imaging agents and / or therapeutic agents for targeted cancer radiotherapy.

[0014] In a first aspect, the disclosure encompasses a theranostic agent having the formula, a complex, anion, or a salt of this formula:

[0015] [ka]

[0016] R1 comprises a chelating moiety, a is 0 or 1, n is an integer from 12 to 21, and R2 comprises a moiety that targets prostate-specific membrane antigen (PSMA).

[0017] In some embodiments, n is 12.

[0018] In some embodiments, n is 13.

[0019] In some embodiments, n is 14.

[0020] In some embodiments, n is 15.

[0021] In some embodiments, n is 16.

[0022] In some embodiments, n is 17.

[0023] In some embodiments, n is 18.

[0024] In some embodiments, n is 19.

[0025] In some embodiments, n is 20.

[0026] In some embodiments, n is 21.

[0027] In some embodiments, theranostic agents are more hydrophobic than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T.

[0028] In some embodiments, theranostic agents are retained in the body of a subject to which they are administered for a longer period of time than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T.

[0029] In some embodiments, theranostic agents remain bound to prostate cancer cells in the subject to which they are administered for a longer period of time than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T.

[0030] In some embodiments, the theranostic agent has greater bioavailability in the body of a subject to which it is administered than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T.

[0031] In some embodiments, the theranostic agent is excreted more abundantly via the liver (and less abundantly via the kidney) from a subject to which it is administered compared to PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T.

[0032] In some embodiments, theranostic agents bind to salivary gland tissue of a subject to which they are administered to a lesser extent than PSMA-11, PSMA-617, or PSMA I&T.

[0033] In some embodiments, theranostic agents bind to renal tissue of a subject to which they are administered to a lesser extent than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T.

[0034] In some embodiments, the chelating moiety is chelated to a metal atom. In some such embodiments, the metal atom is in the form of a metal cation. In some such embodiments, the chelating moiety is anionic and is selected such that the entire theranostic agent is electrically neutral.

[0035] In some embodiments, the metal atom is a positron or single photon emitting metal isotope, or an alpha, beta or Auger emitting metal isotope.

[0036] In some embodiments, the metal atom is a metal isotope that emits positrons or single photons.Such isotopes are particularly suitable for use in imaging applications.Non-limiting examples of such isotopes include Ga-66, Cu-64, Y-86, Co-55, Zr-89, Sr-83, Mn-52, As-72, Sc-44, Sc-43, Ti-45, Tb-152, La-132, La-133, Ce-134, Ga-67, In-111, or Sm-153, Lu-177, or Tc-99m, etc.

[0037] In some embodiments, the metal atom is an alpha, beta, or Auger emitting metal isotope. Such isotopes are particularly suitable for use in targeted radiotherapy applications. Non-limiting examples of such metal isotopes include Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, Sc-47, Sm-153, Tb-161, Tb-149, Bi-213, Bi-212, or Th-227.

[0038] In some embodiments, the chelating moiety is selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) and its derivatives, 1,4,7-triazacyclononane-1,4-diacetic acid (NODA) and one of its derivatives, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and one of its derivatives, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid ( DOTA) or one of its derivatives, 1,4,7-triazacyclononane, 1-glutaric acid-4,7-diacetic acid (NODAGA) or one of its derivatives, 1,4,7,10-tetraazacyclodecane, 1-glutaric acid-4,7,10-triacetic acid (DOTAGA) or one of its derivatives, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) or one of its derivatives, 1,4,8, 11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A) or one of its derivatives, diethylenetriaminepentaacetic acid (DTPA), its diester, or one of its derivatives, 2-cyclohexyldiethylenetriaminepentaacetic acid (CHX-A"-DTPA) or one of its derivatives, 2-(4-isothiatobenzyl)-1,2,7,10,13-hexaazacyclooctadecane-1,4,7,10,13,16-hexaacetic acid (HEHA) or one of its derivatives, deforoxamine (DFO) or one of its derivatives, 1,2-[[6-carboxypyridin-2-yl]methylamino]ethane (H2dedpa) or one of its derivatives, HOPO or one of its derivatives, MACROPA or one of its derivatives, or DADA or one of its derivatives. DADA has the following structure:

[0039] [ka]

[0040] In some embodiments, a is 1. In other embodiments, a is 0.

[0041] In some embodiments, R1 is the following structure or anion thereof:

[0042]

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[0043]

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[0044]

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[0045]

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[0046]

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[0047]

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[0048]

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[0049]

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[0050]

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[0051]

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[0052]

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[0053] [ka]

[0054] [ka]

[0055] [ka]

[0056] In some embodiments, the PSMA targeting moiety includes a urea-based PSMA targeting moiety, a thiol-based PSMA targeting moiety, or a phosphorus-based PSMA binding moiety.

[0057] In some embodiments, the PSMA targeting moiety comprises a Glu-Urea-LysPSMA binding motif.

[0058] In some such embodiments, R2 is of the following structure:

[0059] [ka]

[0060] In some embodiments, the PSMA targeting moiety comprises a phosphoramidate PSMA targeting moiety.

[0061] In some such embodiments, R2 is of the following structure:

[0062] [ka]

[0063] In a second aspect, the disclosure encompasses a composition comprising the theranostic agent described above, together with a pharma- ceutically acceptable carrier. In some embodiments, the composition does not include a specific albumin binder.

[0064] In a third aspect, the present disclosure includes a method for treating cancer associated with increased PSMA expression in a subject. The method includes administering to a subject having cancer an effective amount of the above-mentioned theranostic agent, the theranostic agent comprising a metal atom chelated to a chelating moiety, the metal atom being an alpha, beta, or Auger emitting metal isotope. As a result of carrying out this step, the subject's cancer is successfully treated.

[0065] In some embodiments, the cancer being treated is prostate cancer or breast cancer. In some embodiments, the cancer being treated is prostate cancer.

[0066] In some embodiments, the metal isotope is Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, Sc-47, Sm-153, Tb-161, Tb-149, Bi-213, Bi-212, or Th-227.

[0067] In some embodiments, the theranostic agent is administered in the absence of an albumen binding agent.

[0068] In some embodiments, the theranostic agent is administered by parenteral, intranasal, sublingual, rectal, or transdermal delivery, hi some such embodiments, the theranostic agent is administered intravenously.

[0069] In some embodiments, the subject is a human.

[0070] In some embodiments, the theranostic agent is retained in the body of a subject to which it is administered for a longer period of time than it would be retained if PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T were administered to the subject.

[0071] In some embodiments, the theranostic agent remains bound to prostate cancer cells in the subject to which it is administered for a longer period of time than it would be bound if PSMA-11, PSMA-617, PSMA-R2, EB-PSMA or PSMA I&T were administered to the subject.

[0072] In some embodiments, the theranostic agent has a bioavailability in the body of a subject to which it is administered that is greater than the bioavailability that PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T would have if administered to the subject.

[0073] In some embodiments, the theranostic agent is excreted hepatically from a subject to which it is administered to a greater extent (and excreted renally to a lesser extent) than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T would be excreted when administered to a subject.

[0074] In some embodiments, theranostic agents bind to the salivary gland tissue of a subject to which they are administered to a lesser extent than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T would bind if administered to the subject.

[0075] In some embodiments, theranostic agents bind to renal tissue of a subject to which they are administered to a lesser extent than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T would bind when administered to the subject.

[0076] In a fourth aspect, the disclosure encompasses a method for inhibiting the proliferation and / or growth of malignant cells associated with increased PSMA expression. The method comprises contacting one or more malignant cells with an effective amount of theranostic agent described above, the theranostic agent comprising a metal atom chelated to a chelating moiety, the metal atom being an alpha, beta, or Auger emitting metal isotope. Performing this step results in the inhibition of the proliferation and / or growth of the malignant cells.

[0077] In some embodiments, the metal isotope is Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, Sc-47, Sm-153, Tb-161, Tb-149, Bi-213, Bi-212, or Th-227.

[0078] In some embodiments, the malignant cell is a malignant prostate cell or a malignant breast cell. In some embodiments, the malignant cell is a malignant prostate cell.

[0079] In some embodiments, the theranostic agent is contacted with one or more malignant prostate cells in the absence of an albumin binding agent.

[0080] In some embodiments, the method is performed in vivo, ex vivo, or in vitro.

[0081] In a fifth aspect, the present disclosure provides a method for detecting or imaging one or more cancer cells associated with increased PSMA expression in a biological sample. The method includes (a) contacting the biological sample with the theranostic agent described above, the theranostic agent comprising a metal atom chelated to a chelating moiety, the metal atom being a positron or single photon emitting metal isotope, whereby the theranostic agent specifically binds to the cancer cells in the biological sample. The method includes (b) identifying individual cells or regions in the biological sample that emit a signal characteristic of the metal isotope. As a result of performing these steps, one or more cancer cells are detected or imaged.

[0082] In some embodiments, the one or more cancer cells are prostate or breast cancer cells. In some such embodiments, the cancer cells are prostate cancer cells.

[0083] In some embodiments, the metal isotope is Ga-66, Cu-64, Y-86, Co-55, Zr-89, Sr-83, Mn-52, As-72, Sc-44, Sc-43, Ti-45, Tb-152, La-132, La-133, Ce-134, Ga-67, In-111, or Sm-153, Lu-177, or Tc-99m.

[0084] In some embodiments, theranostic agents are contacted with the biological sample in the absence of an albumin binding agent.

[0085] In some embodiments, identifying individual cells or regions within the biological sample emitting a signal characteristic of the metal isotope is performed by positron emission tomography (PET) imaging, single photon emission computed tomography (SPECT) imaging, or gamma camera planar imaging.

[0086] In some embodiments, the biological sample is part or all of a subject. In some such embodiments, the subject is a human.

[0087] In some embodiments, the theranostic agent is retained in the subject for a period of time longer than the period of time that PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T are retained when contacted with a biological sample.

[0088] In some embodiments, the theranostic agent remains bound to the prostate cancer cells in the subject for a period of time longer than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T would be bound when contacted with a biological sample.

[0089] In some embodiments, the theranostic agent has a higher bioavailability in a subject than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T would have when contacted with a biological sample. In some embodiments, the theranostic agent is excreted hepatically to a greater extent (and renally to a lesser extent) from a subject than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T would have when contacted with a biological sample.

[0090] In some embodiments, the theranostic agent binds to said salivary gland tissue of the subject to a lesser extent than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T binds when contacted with a biological sample.

[0091] In some embodiments, the theranostic agent binds to renal tissue of the subject to a lesser extent than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA or PSMA I&T binds when contacted with a biological sample.

[0092] In some embodiments, the biological sample is obtained from a subject. In some such embodiments, the subject is a human.

[0093] In a sixth aspect, the present disclosure encompasses a method for diagnosing cancer associated with increased PSMA expression in a subject.The method includes the steps outlined above, in which a biological sample is obtained from a subject, a part of a subject, or the whole subject.If cancer cells are detected or imaged, the subject is diagnosed with cancer.

[0094] In some embodiments, the cancer is prostate cancer or breast cancer, hi some such embodiments, the cancer is prostate cancer.

[0095] In a seventh aspect, the present disclosure encompasses a method for monitoring the effectiveness of cancer treatment in a human subject, wherein the cancer is associated with increased PSMA expression.The method comprises carrying out the detection / imaging steps outlined above on a biological sample at two or more different times, the biological sample being obtained from a part or the whole of the subject.The change in the intensity of the signal characteristic of the metal isotope between the two or more different times correlates with the effectiveness of the cancer treatment.

[0096] In some embodiments, the cancer is prostate cancer or breast cancer, hi some such embodiments, the cancer is prostate cancer.

[0097] In some embodiments, the cancer treatment being monitored is chemotherapy and / or radiation therapy.

[0098] In an eighth aspect, the present disclosure provides a method of treating a cancer associated with increased PSMA expression in a subject, the method comprising the steps outlined above, wherein the biological sample is part or all of the subject, and then irradiating identified individual cells or regions within the subject with an external radiation therapy beam.

[0099] In some embodiments, the cancer is prostate cancer or breast cancer, hi some such embodiments, the cancer is prostate cancer.

[0100] In a ninth aspect, the disclosure encompasses a method for determining a therapeutic dose of a theranostic agent for treating a cancer in a subject associated with increased PSMA expression, the method comprising: (a) administering to the subject a detection-enhancing dose of the theranostic agent described above, the theranostic agent used in the detection-enhancing dose comprising a metal atom chelated to a chelating moiety, the metal atom being a positron or single-photon emitting metal isotope; (b) subsequently detecting a signal from one or more prostate cancer cells in the subject that is characteristic of the metal isotope of the theranostic agent used in the detection-enhancing dose; and (c) determining a therapeutic dose of the theranostic agent from the intensity of the signal detected in step (b).

[0101] In some embodiments, the cancer is prostate cancer or breast cancer, hi some such embodiments, the cancer is prostate cancer.

[0102] In some embodiments, the metal isotope of the theranostic agent used in the detection enhancing dose is Ga-66, Cu-64, Y-86, Co-55, Zr-89, Sr-83, Mn-52, As-72, Sc-44, Sc-43, Ti-45, Tb-152, La-132, La-133, Ce-134, Ga-67, In-111, or Sm-153, Lu-177, or Tc-99m.

[0103] In some embodiments, detecting a signal from one or more prostate cancer cells in the subject that is characteristic of the metal isotope of the theranostic agent used in the detection-enhancing dose is performed by positron emission tomography (PET) imaging, single photon emission computed tomography (SPECT) imaging, or gamma camera planar imaging.

[0104] In some embodiments, the method further comprises administering to the subject a determined therapeutic dose of theranostic agent, wherein the theranostic agent used in the therapeutic dose comprises a metal atom chelated to a chelating moiety, and the metal atom is an alpha, beta, or Auger emitting metal isotope.

[0105] In some embodiments, the metal isotope of the theranostic agent used in a therapeutic dose is Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, Sc-47, Sm-153, Tb-161, Tb-149, Bi-213, Bi-212, or Th-227.

[0106] In a tenth aspect, the disclosure encompasses a method of treating a cancer in a subject associated with increased PSMA expression, comprising: (a) administering to the subject a detection-enhancing dose of the theranostic agent described above, wherein the theranostic agent used in the detection-enhancing dose comprises a metal atom chelated to a chelating moiety, the metal atom being a positron or single photon emitting metal isotope; (b) subsequently detecting a signal from one or more cancer cells in the subject that is characteristic of the metal isotope of the theranostic agent used in the detection-enhancing dose; (c) determining a therapeutic dose of the theranostic agent from the intensity of the signal detected in step (b); and (d) administering to the subject a determined therapeutic dose of the theranostic agent described above, wherein the theranostic agent used in the therapeutic dose comprises a metal atom chelated to a chelating moiety, the metal atom being an alpha, beta, or Auger emitting metal isotope. As a result of performing these steps, the cancer in the subject is treated.

[0107] In some embodiments, the cancer is prostate cancer or breast cancer, hi some such embodiments, the cancer is prostate cancer.

[0108] In some embodiments, the metal isotope of the theranostic agent used in the detection enhancing dose is Ga-66, Cu-64, Y-86, Co-55, Zr-89, Sr-83, Mn-52, As-72, Sc-44, Sc-43, Ti-45, Tb-152, La-132, La-133, Ce-134, Ga-67, In-111, or Sm-153, Lu-177, or Tc-99m.

[0109] In some embodiments, detecting a signal from one or more cancer cells in the subject that is characteristic of the metal isotope of the theranostic agent used in the detection-enhancing dose is performed by positron emission tomography (PET) imaging, single photon emission computed tomography (SPECT) imaging, or gamma camera planar imaging.

[0110] In some embodiments, the metal isotope of the theranostic agent used in a therapeutic dose is Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, Sc-47, Sm-153, Tb-161, Tb-149, Bi-213, Bi-212, or Th-227.

[0111] In an eleventh aspect, the present disclosure provides one or more of the theranostic agents described above for use in imaging cancer associated with increased PSMA expression or malignant cells associated with increased PSMA expression.

[0112] In some embodiments, the cancer or cancer cells are prostate cancer or breast cancer. In some embodiments, the cancer or cancer cells are prostate cancer.

[0113] In a twelfth aspect, the disclosure provides one or more of the theranostic agents described above for use in treating a cancer associated with increased PSMA expression.

[0114] In some embodiments, the cancer is prostate cancer or breast cancer, hi some such embodiments, the cancer is prostate cancer.

[0115] In a thirteenth aspect, the disclosure provides one or more of the theranostic agents described above for use in treating a cancer associated with increased PSMA expression, or for use in the manufacture of a theranostic agent for treating or imaging a cancer associated with increased PSMA expression.

[0116] In some embodiments, the cancer is prostate cancer or breast cancer, hi some such embodiments, the cancer is prostate cancer.

[0117] Other objects, features, and advantages of the present invention will become apparent from a study of the specification, claims, and drawings. [Brief description of the drawings]

[0118] [Figure 1] FIG. 1 shows time-lapse PET images of ICR mice after injection with 86Y-PMSA-C12. [Diagram 2] FIG. 2 shows time-lapse PET images of ICR mice after injection with 86Y-PMSA-PhC18. [Diagram 3] FIG. 3 shows a competitive binding assay of PSMA-617 and PSMA-C12 in LNCap cells using 86Y as the radioligand. [Figure 4] Figures 4A-4C show the relative distribution of 86Y-PSMA-617 (4A), 86Y-PSMA-C12 (4B), or 86Y-PSMA-PhC18 (4C) in PC3-PIP tumor xenografts. T: tumor, H: heart, L: liver, K: kidney, B: bladder. [Diagram 5]Figure 1 shows region of interest analysis (biodistribution analysis) of PET / CT images in nude mice bearing PC3-PIP tumor xenografts intravenously injected with 86Y-PSMA-617, 86Y-PSMA-C12, or 86Y-PSMA-PhC18 and scanned up to 72 hours post-injection. 86Y-PSMA-PhC18 has been shown to have a long blood circulation with a half-life of 11.7 and minimal renal clearance. 86Y-PSMA-PhC18 tumor uptake plateaus at 24 hours post-injection. [Figure 6] Figure 6 shows the ex vivo biodistribution after the final imaging timepoint, 24 h post-injection in PC3-PIP mice intravenously injected with 86Y-PSMA-617, 86Y-PSMA-C12, and 72 h post-injection in mice receiving 86Y-PSMA-PhC18. [Figure 7] Figures 7A-7C show PET / CT imaging of nude mice bearing low-PSMA-expressing LNCap tumor xenografts intravenously injected with 86Y-PSMA-617 (7A), 86Y-PSMA-C12 (7B), or 86Y-PSMA-PhC18 (7C) and scanned up to 72 hours post-injection. [Figure 8] Figure 8 shows region of interest analysis (biodistribution analysis) of PET / CT images scanned up to 72 hours after intravenous injection of 86Y-PSMA-617, 86Y-PSMA-C12, or 86Y-PSMA-PhC18 in nude mice bearing LNCap tumor xenografts. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0119] [I. Overview] This disclosure is not limited to the particular methodology, protocols, materials, and reagents described, as these may vary. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention.

[0120] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Similarly, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably. The term "comprising" and variations thereof do not have a limiting meaning where these terms appear in the description and claims. Thus, the terms "comprising," "including," and "having" can be used interchangeably.

[0121] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs.All publications and patents specifically mentioned in this specification are incorporated by reference for all purposes, including the description and disclosure of chemicals, instruments, statistical analysis, and methodology reported in the publications that may be used in connection with this invention.All references cited in this specification should be interpreted as indicating the level of ordinary skill in the art.

[0122] The present disclosure encompasses the theranostic agents described herein (including intermediates) in their pharma- ceutically acceptable forms, including isomers (e.g., diastereomers and enantiomers), tautomers, salts (including their anionic and cationic components), solvates, polymorphs, prodrugs, and the like. In particular, where a theranostic agent is optically active, the present invention specifically includes each of the enantiomers of the theranostic agent, as well as racemic mixtures of the enantiomers. The term "compound" or "theranostic agent" includes any or all of such forms, whether or not explicitly stated (although in some cases a "salt," "complex," or "anion" thereof may be explicitly stated).

[0123] As used herein, "pharmacologically acceptable" means a theranostic agent or composition or carrier suitable for administration to a subject to achieve the treatment described herein without unduly toxic side effects in light of the needs of the treatment.

[0124] As used herein, the term "effective amount" refers to an amount or dosage of a theranostic agent that will elicit the biological or medical response in a subject, tissue, or cell that is desired by a researcher, veterinarian, medical doctor, or other clinician.

[0125] As used herein, "pharmaceutically acceptable carriers" include any dry powders, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonicity agents, absorption delaying agents, and the like. A pharmaceutically acceptable carrier is a substance useful for the purpose of administering a compound in the method of the present invention, and is preferably non-toxic, and may be a solid, liquid, or gaseous substance that is otherwise inert, pharmaceutically acceptable, and compatible with the compound of the present invention. Examples of such carriers include, but are not limited to, oils such as mannitol, corn oil, buffers such as PBS, saline, polyethylene glycol, glycerin, polypropylene glycol, amides such as dimethylsulfoxide, dimethylacetamide, proteins such as albumin, detergents such as Tween 80, mono- and oligopolysaccharides such as glucose, lactose, cyclodextrin, and starch.

[0126] As used herein, the term "administer" or "administration" refers to providing a theranostic agent or pharmaceutical composition of the invention to a subject suffering from or at risk for the disease or condition to be treated or prevented.

[0127] In pharmacology, the route of administration is the way a drug is introduced into the body. Routes of administration are generally classified according to where the substance is applied. Common examples are oral and intravenous. Routes of administration can also be classified according to where the target of action is. The action can be local (topical), enteral (acting systemically but delivered via the digestive tract), parenteral (acting systemically but delivered via a route other than the digestive tract), or via the lungs via inhalation.

[0128] Topical administration emphasizes local effect or delayed release, for example, a substance can be applied directly to the location where its action is desired. However, the term topical administration may also be defined as application to a local site or surface of a body part without necessarily involving the target effect of the substance, and this classification is rather a variation of the classification based on the application site. In enteral administration, the desired effect is generally systemic (non-local) and the substance is administered via the digestive tract. In parenteral administration, the desired effect is generally systemic and the substance is administered by a route other than the digestive tract.

[0129] Non-limiting examples of topical administration include epicutaneous (application to the skin), e.g., for allergy testing and typical local anesthetics, inhalation administration such as, e.g., asthma medications, enemas such as contrast agents for intestinal imaging, eye drops (on the conjunctiva) such as, e.g., antibiotics for conjunctivitis, ear drops such as antibiotics and corticosteroids for otitis externa, and via mucous membranes internally.

[0130] Enteral administration is administration that involves any part of the digestive tract and affects the entire body. Examples include many drugs administered by mouth (oral), in tablets, capsules, drops, gastrostomy, duodenal fistula, and gastrostomy, as well as enteral nutrition, rectal administration, and various drugs administered as suppositories.

[0131] Examples of parenteral administration include intravenous administration (injection into a vein), e.g., many drugs, total parenteral nutrition, intra-arterial administration (injection into an artery), e.g., vasodilators in the treatment of vasospasm, thrombolytics for the treatment of embolism, intraosseous injection (injection into the bone marrow), intramuscular injection, intracerebral injection (injection into the brain parenchyma), intraventricular injection (injection into the ventricular system), intrathecal injection (injection into the spinal canal), subcutaneous injection (injection under the skin), etc. Among these, intraosseous injection is essentially an indirect venous access, since the bone marrow is directly drained into the venous system. In emergency medicine and pediatrics, intraosseous injection is sometimes used for drugs and infusions when intravenous access is difficult.

[0132] As used herein, the term "intraperitoneal injection" or "IP injection" refers to the injection of a substance into the peritoneum (body cavity). IP injections are more commonly used in animals than in humans. In general, IP injections are preferred when large volumes of blood substitute fluid are required or when hypotension or other problems prevent the use of suitable blood vessels for intravenous injection.

[0133] As used herein, the term "PSMA-11" refers to a PSMA-targeting ligand known in the art having the following structure:

[0134] [ka]

[0135] As used herein, the term "PSMA-617" refers to a PSMA-targeting ligand known in the art having the following structure:

[0136] [ka]

[0137] As used herein, the term "PSMA I&T" refers to a PSMA targeting ligand known in the art having the following structure:

[0138] [ka]

[0139] [II. Nanotechnology drugs] In certain aspects, the present disclosure is directed to a PSMA-targeted theranostic agent, which can be optionally labeled with a radioactive metal isotope, for detecting / imaging cancer cells associated with increased PSMA expression in a subject or biological sample, or for treating cancer associated with increased PSMA expression in a subject. The theranostic agent comprises a PSMA targeting moiety and a chelating moiety capable of chelating a radioactive metal isotope. These two moieties are linked by a linker comprising an aliphatic chain. By varying the length of the aliphatic chain, the pharmacokinetics, bioavailability, circulating half-life, and other parameters of the disclosed theranostic agent can be adjusted and optimized.

[0140] The present disclosure is not limited to a particular type of cancer, but instead encompasses compositions and methods for detecting and / or treating any type of cancer associated with increased PSMA expression. Non-limiting examples of such cancers include prostate cancer and breast cancer.

[0141] A. Radioactive Metal Isotopes for Cancer Treatment For the disclosed methods of therapeutically treating cancers associated with increased PSMA expression, any radioactive metal isotope known to emit ionizing radiation in a form that will result in the death of cancer cells (e.g., prostate cancer cells) that bind to or take up the theranostic agent can be incorporated into the theranostic agent by chelation. In some embodiments, the radioactive metal isotope emits its ionizing radiation in a form that minimizes damage to tissues other than the cells that take up or bind the labeled theranostic agent.

[0142] Non-limiting examples of radioactive metal isotopes that may be used include Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, Sc-47, Sm-153, Tb-161, Tb-149, Bi-213, Bi-212, or Th-227.

[0143] In some embodiments, the longer retention of the currently disclosed theranostic compounds in cancer cells and tumors provides a synergistic advantage when combined with some of the radioisotopes contemplated for use herein that have longer half-lives. In other words, by combining a therapeutic radioisotope (e.g., one that emits ionizing radiation) with a longer half-life with a targeting moiety disclosed herein that has longer retention in cancer cells / tumors, the resulting theranostic agent can more effectively treat cancer by providing an extended therapeutically effective treatment period compared to other treatment modalities. As a result, subjects administered these theranostic agents can receive effective treatment with either a reduced dose of the therapeutic radioisotope and / or a reduced number of doses of the theranostic agent.

[0144] In certain embodiments, theranostic agents for cancer treatment include long-lived isotopes, where the half-life of the isotope is at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 days. For example, the radioisotope has a half-life of 6 days. 177 Lu, or a half-life of 10 days 225 Ac, or a half-life of 20 days 227 It can be Th.

[0145] B. Radioactive Metal Isotopes for Malignant Solid Tumor Detection / Imaging For the disclosed method of detecting / imaging cancer associated with increased PSMA expression, any radioactive metal isotope known to emit radiation in a form that is easily detectable by conventional imaging means can be incorporated into the theranostic agent by chelation. Non-limiting examples of "conventional imaging means" include gamma ray detection, PET scan, and SPECT scan. Non-limiting examples of radioactive metal isotopes that can be used include Ga-66, Cu-64, Y-86, Co-55, Zr-89, Sr-83, Mn-52, As-72, Sc-44, Sc-43, Ti-45, Tb-152, La-132, La-133, Ce-134, Ga-67, In-111, or Sm-153, Lu-177, or Tc-99m.

[0146] In one embodiment, perhaps another claim could be more sensitive detection of primary prostate disease, since the bladder would not obscure the lesions, given that the drug is not excreted renally.

[0147] <C.PSMA target site> The disclosed compositions and methods can use any moiety that effectively targets PSMA. Non-limiting examples of PSMA targeting moieties that can be used include thiol-based, urea-based, and phosphorus-based PSMA targeting moieties, such as those disclosed by Machulkin et al. (E. Machulkin, Yan A. Ivanenkov, Anastasia V. Aladinskaya, Mark S. Veselov, Vladimir A. Aladinskiy, Elena K. Beloglazkina, Victor E. Koteliansky, Artem G. Shakhbazyan, Yuri B. Sandulenko & Alexander G. Majouga (2016) Small-molecule PSMA ligands. Current state, SAR and perspectives, Journal of Drug Targeting, 24:8, 679-693, DOI: 10.3109 / 1061186X.2016.1154564), which is incorporated herein by reference.

[0148] D. NON-LIMITING EXEMPLARY THERAPEUTIC AGENTS The disclosed structures utilize a scaffold containing a chelating moiety to which an aliphatic hydrocarbon chain and a PSMA targeting moiety are attached. Once synthesized, the theranostic agent must possess formulation properties that make it suitable for injection while retaining prostate tumor selectivity. Below are shown non-limiting exemplary series of two different theranostic agents, PSMA-C12 and PSMA-PhC18. On the left side of the two structures is the chelating moiety to which the radioactive metal isotope is chelated to produce the final imaging or therapeutic agent. The aliphatic linker is in the center of each structure, and the PSMA targeting moiety is on the right side of each structure.

[0149] [ka]

[0150] [ka]

[0151] E. METHODS OF SYNTHESIS OF EXEMPLARY THERAPEUTIC AGENTS The synthesis of PSMA-targeting lysine-ureido-glutamic acid ligand 2 is shown in Scheme 1. Synthesis began with the di-tert-butyl ester of L-glutamic acid via reaction with triphosgene to form an intermediate isocyanate, followed by reaction with Nε-ZL-lysine t-butyl ester to provide compound 1 according to a published procedure (Ivanenkov IA et al., Bioorg Med Chem Lett, 2019, 29, 1246-1255). Removal of the Cbz group of 1 by hydrogenation afforded the core ligand 2.

[0152] [ka]

[0153] The synthesis scheme of PSMA-C12 is shown below. In the first step of the synthesis, DOTA tris-tert-butyl ester was coupled to benzyl 12-aminododecanoate ((Ivanenkov IA et al., Bioorg Med Chem Lett, 2019, 29, 1246-1255) using COMU as a coupling agent. The coupled product 3 was subjected to catalytic hydrogenation to remove the benzyl protecting group. The resulting carboxylic acid 4 was coupled with amino compound 2 in the presence of PPAA (n-propylphosphonic anhydride) to give compound 5 in which all carboxy groups were protected as tert-butyl esters. Global t-butyl ester deprotection was performed using 4 M hydrochloric acid in dioxane to give PSMA C12 compound 6 as the hydrochloride salt.

[0154] [ka]

[0155] The synthesis of PSMA PhC18 compound is shown in Scheme 3. Reaction of core ligand 2 with 18-(p-iodophenyl)-octadecanoic acid via PPAA gave compound 7. The aromatic iodide in 7 was replaced with azide by CuI / N,N'-dimethylethylenediamine catalysis (Andersen J et al., Synlett, 2005, 2209-2213). Reduction of the aromatic azide in 8 by catalytic hydrogenation gave aromatic amine 9. This compound was coupled with DOTA tris-tert-butyl ester to give the fully protected PSMA PhC18 precursor 10. All t-Bu ester groups were removed with 4 M hydrochloric acid in dioxane to give PSMA PhC18 compound 11 as the hydrochloride salt.

[0156] [ka]

[0157] F. Charge Balance of Theranostic Agents As noted throughout this disclosure, many different known chelating moieties may be used in the disclosed theranostic agents. In preferred embodiments where a metal radioisotope is chelated to the chelating moiety, the resulting complex is overall electrically neutral. Typically, the selected metal radioisotope is in the form of a positively charged cation, and therefore the chelating moiety is selected to have a negative charge equal in magnitude to the positive charge of the metal cation.

[0158] G. Adjusting the Length of the Aliphatic Hydrocarbon Linker to Tune Desired Properties The aliphatic hydrocarbon chain used as the linker of the disclosed theranostic agents is key to tailoring and optimizing the properties of theranostic agents. The linker length ranges from 12 to 21 carbons, and it has been found that shortening and / or lengthening the carbon chain can alter many relevant chemical and biological properties of the theranostic agent. Thus, the length of the linker can be selected to optimize such properties for a given particular application.

[0159] Essentially, altering the length of the aliphatic hydrocarbon chain impacts the hydrophobicity of the theranostic agent. Specifically, lengthening the chain from 12 to 21 carbon atoms increases the overall hydrophobicity of the theranostic agent. This fundamental change correlates with many of the relevant biological properties of the disclosed theranostic agents and has been found to confer surprising advantages over previously known PSMA-targeting ligands such as PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, and PSMA I&T.

[0160] In one example, it has been found that increasing the length of the hydrocarbon chain increases the circulating half-life of the theranostic agent in the administered subject, and if the agent is retained in the subject for a longer period of time, a single administration can provide prostate cancer treatment and facilitate prostate cancer detection for a longer period of time.

[0161] In a second related example, it has been found that increasing the length of the hydrocarbon chain increases the time that the theranostic agent remains bound to prostate cancer cells in a subject, again extending the time that a single dose can provide an effective prostate cancer treatment and facilitating detection of prostate cancer.

[0162] In a third example, it has been found that increasing the length of the hydrocarbon chain increases the bioavailability of the theranostic agent in the subject to which it is administered. Furthermore, the theranostic agent having the disclosed linker does not need to be administered with an albumin binder, further improving bioavailability compared to previously known PSMA targeting ligands. Increased bioavailability means that a smaller effective dose of the theranostic agent is required, which is particularly advantageous when administering radioactive (and potentially toxic) metals to the subject.

[0163] In the fourth example, it was found that increasing the length of the hydrocarbon chain affects the excretion pathway of the theranostic agent. When the hydrocarbon chain length is 12, the theranostic agent is mainly excreted via the kidney, as reported for known PSMA targeting ligands. However, as the hydrocarbon chain length increases, the theranostic agent is more excreted via the liver (and less via the kidney). Thus, the length of the hydrocarbon chain of the theranostic agent can be selected to obtain an optimal combination of renal and hepatic excretion.

[0164] In a fifth example, it was found that increasing the length of the hydrocarbon chain reduces the degree of off-target binding of the theranostic agent. Specifically, it was found that the theranostic agents with longer hydrocarbon chains do not collect or bind to the salivary gland or kidney tissue of the subjects to whom they are administered, as previously reported for known PSMA targeting ligands. Thus, the disclosed theranostic agents have an improved prostate cancer targeting profile.

[0165] Finally, in alpha particle therapy, it is important to deliver the alpha emitting radioisotope as close as possible to the targeted prostate cancer cells. The disclosed theranostic agents do not have the bulky linkers (typically containing one or more phenyl groups) used in previously known PSMA targeting ligands, so that the disclosed theranostic agents can be effectively optimized for alpha particle based therapy.

[0166] In some embodiments, it is contemplated that the theranostic agents disclosed herein provide more sensitive detection of primary prostate disease, given that the agents are not excreted renaly, and therefore the bladder does not obscure the lesion.In this manner, it is contemplated that a method of treating an individual suspected of having prostate cancer may include administering an effective amount of the theranostic agent disclosed herein, and detecting the individual's primary prostate disease using an appropriate mode of detection according to the radioisotope employed.

[0167] In some embodiments, dual function theranostic agents are contemplated, in which a radioisotope chelated to the theranostic agent has both utility as an imaging agent and as an anti-cancer therapeutic agent.

[0168] H. Dosage Forms and Methods of Administration Any route of administration may be suitable for administering the disclosed theranostic agents to a subject. In one embodiment, the disclosed theranostic agents may be administered to a subject via intravenous injection. In another embodiment, the disclosed theranostic agents may be administered to a subject via parenteral, nasal, sublingual, rectal, or any other suitable systemic delivery, such as transdermal administration.

[0169] In another embodiment, the disclosed theranostic agents can be administered to a subject through the nasal system or mouth, for example, by inhalation.

[0170] In another embodiment, the disclosed theranostic agents may be administered to a subject via intraperitoneal or IP injection.

[0171] In certain embodiments, the disclosed theranostic agent can be provided as a pharmaceutically acceptable salt.However, other salts can be useful in the preparation of theranostic agents or their pharmaceutically acceptable salts.Suitable pharmaceutically acceptable salts include, but are not limited to, the acid addition salts that can be formed by mixing a solution of theranostic agent with a solution of a pharmaceutically acceptable acid, such as, for example, hydrochloric acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid, or phosphoric acid.

[0172] When the disclosed theranostic agents have at least one asymmetric center, they can exist as enantiomers accordingly.When the disclosed alkylphosphocholine analogs have two or more asymmetric centers, they can further exist as diastereomers.All such isomers and mixtures thereof, in any proportion, are encompassed within the scope of the present disclosure.

[0173] The disclosure also includes methods of using pharmaceutical compositions comprising one or more of the disclosed theranostic agents in association with a pharma- ceutically acceptable carrier.Preferably, these compositions are in unit dosage form, such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered dose aerosols or liquid sprays, drops, ampoules, auto-injector devices or suppositories, unit dosage forms for parenteral, nasal, sublingual, or rectal administration, or unit dosage forms for administration by inhalation or pneumoperitoneum.

[0174] To prepare solid compositions such as tablets, the primary active ingredient is mixed with a pharma- ceutically acceptable carrier, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, such as water, to form a solid preformulation composition containing a homogenous mixture for the compound of the present invention or a pharma- ceutically acceptable salt thereof. When such a preformulation composition is referred to as homogenous, it is meant that the active ingredient is uniformly dispersed throughout the composition, so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain 1 to 100 mg, e.g., 1, 2, 5, 10, 25, 50, or 100 mg of active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage that provides the advantage of prolonged action. For example, a tablet or pill may consist of an inner dosage component and an outer dosage component, the latter being in the form of an encapsulation over the former. The two components may be separated by an enteric layer, which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, cellulose acetate, and the like.

[0175] Liquid forms into which the theranostic agents can be incorporated for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginic acid, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, or gelatin.

[0176] The disclosed theranostic agents are particularly useful when formulated in the form of pharmaceutical injectable dosage forms, including in combination with an injectable carrier system.As used herein, injectable dosage forms and infusion dosage forms (i.e., parenteral dosage forms) include, but are not limited to, liposomal injections or lipid bilayer vesicles having phospholipids that encapsulate active drug substances.Injectables include sterile formulations intended for parenteral use.

[0177] There are five different classes of injectables as defined by the USP: emulsions, lipids, powders, solutions, and suspensions. Emulsion injectables include emulsions consisting of sterile, pyrogen-free preparations intended for parenteral administration. Lipid complexes and powders for solution injections are sterile preparations intended to be reconstituted to form solutions for parenteral administration. Powders for suspension injections are sterile preparations intended to be reconstituted to form suspensions for parenteral use. Lyophilized powders for liposomal suspension injections are sterile lyophilized preparations intended to be reconstituted for parenteral use, formulated in a manner that allows the incorporation of liposomes, such as lipid bilayer vesicles with phospholipids used to encapsulate the active drug within the lipid bilayer or aqueous space, which upon reconstitution can form a formulation. Lyophilized powders for solution injections are dosage forms intended for solutions prepared by freeze-drying ("lyophilization"), a process in which water is removed from a frozen product at extremely low pressure, followed by the addition of liquid to create a solution that meets all the requirements for injection. Lyophilized powders for suspension injections are liquid preparations intended for parenteral use containing solids suspended in a suitable fluid medium and conforming in all respects to the requirements of a sterile suspension; pharmaceutical agents intended for suspension are prepared by lyophilization. Solution injections include liquid preparations containing one or more drug substances dissolved in a suitable solvent or mixture of mutually miscible solvents suitable for injection.

[0178] Solution concentrated injections include sterile preparations for parenteral use that, upon addition of a suitable solvent, result in a solution that meets the requirements for injection in all respects. Suspension injections are liquid preparations (suitable for injection) that contain solid particles dispersed throughout the liquid phase, where the particles are insoluble, and an oil phase dispersed throughout the aqueous phase, or vice versa. Suspension liposome injections are liquid preparations (suitable for injection) that have an oil phase dispersed throughout the aqueous phase in such a way that liposomes (lipid bilayer vesicles that typically contain phospholipids used to encapsulate active drugs within the lipid bilayer or aqueous space) are formed. Suspension ultrasonic injections are liquid preparations (suitable for injection) that contain solid particles dispersed throughout the liquid phase, where the particles are insoluble. Additionally, they may be sonicated as a gas bubbled through the suspension, resulting in the formation of microspheres with solid particles.

[0179] Parenteral carrier systems may contain one or more pharma- ceutically suitable excipients, such as solvents and cosolvents, solubilizing agents, wetting agents, suspending agents, thickening agents, emulsifying agents, chelating agents, buffers, pH adjusting agents, antioxidants, reducing agents, antimicrobial preservatives, bulking agents, protectants, tonicity adjusting agents, and special additives.

[0180] The following examples are intended for illustrative purposes only and are not intended to limit the scope of the invention in any way. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and following examples and fall within the scope of the appended claims. EXAMPLES

[0181] [III. Examples] Example 1: Proof of concept for in vivo imaging (summary): In this example, PSMA-C12 and PSMA PhC-18 ( 86We demonstrate that Y (radioactively labeled with Y) is taken up by and retained within ICR mice, providing proof of concept for using the disclosed theranostic agents as targeted radiotherapy and / or imaging agents. Additionally, differences in the length of the hydrocarbon chain between the two compounds were found to affect properties associated with the use of theranostic agents. Thus, as outlined above, proof of concept has been obtained for altering the length of the hydrocarbon chain to tailor and / or optimize the disclosed theranostic agents for specific applications.

[0182] (Materials, Methods, Results): The structures of the PSMA-C12 and PSMA-PhC18 compounds are shown above. Hydrophobicity was varied by changing the number of members in the aliphatic portion of the molecule.

[0183] Compounds PSMA-C12 and PSMA-PhC18 were dissolved in water at a concentration of 1–2 mg / mL. Radiolabeling with Y-86 was carried out in NaOAc buffer (pH 5.0) at 90–95 °C for 30 min to 1 h with constant stirring. 86 Ten micrograms of compound per mCi of Y were used, resulting in quantitative radiochemical yields. Purification of the compounds was performed using reversed-phase solid-phase chromatography, and the purified compounds were redissolved in physiological injection media (e.g., saline). Quality control was performed using reversed-phase HPLC.

[0184] For PET / CT imaging studies, 100–250 μCi 86 Y-PSMA-C12 and 86 Y-PSMA-PhC18 was administered intravenously to normal ICR mice, and the mice were scanned 0, 1, and 2 days after injection. The results are shown in Figure 1 ( 86 ) and Fig. 2 ( 86 The blood flow dynamics were analyzed through cardiac region of interest analysis.

[0185] PET imaging revealed significantly different hemodynamic and excretion profiles between the two compounds. 86 Y-PSMA-C12 acted similarly to the “classical” PSMA inhibitors, with a short circulating half-life and renal excretion, whereas 86 Y-PSMA-PhC18 was shown to have a long circulating half-life and long hepatic and biliary excretion. 86 Y-PSMA-PhC18 is the only PSMA inhibitor that exhibits long circulation without albumin binding and is primarily excreted through the liver, features that give it distinct advantages over other PSMA ligands known so far as prostate cancer theranostic agents.

[0186] Example 2 Comparative study of therapeutic drugs In this example, the properties of PSMA-617, PSMA-C12, and PSMA PhC-18 theranostic compounds were compared.

[0187] (Materials, Methods, Results): See above for structures of PSMA-C12 and PSMA-PhC18 compounds.

[0188] Compounds PSMA-617, PSMA-C12, and PSMA-PhC18 were incubated with Lu-177 or 86 It was radiolabeled with Y. Quality control was performed using reverse phase HPLC.

[0189] Table 1 shows 177 Lu-PSMA-617, 177 Lu-PSMA-C12, and 177 The partition coefficient (logP) and partition coefficient (logD) of Lu-PSMA-PhC18 are shown. 177 Lu-PSMA-617 and 177 Lu-PSMA-C12 has similar hydrophobicity, but 177 Lu-PSMA-PhC18 is two orders of magnitude more hydrophobic.

[0190] [Table 1]

[0191] 86 A competitive binding assay was performed in LNCap cells (PSMA-positive, androgen-sensitive human prostate adenocarcinoma cells) using Y as the radioligand. As shown in Figure 3, 86 Y-PSMA-617 and 86 Y-PSMA-C12 had median inhibitory concentrations (IC ) of 39.5 nM and 58.2 nM, respectively. 50 ) and showed similar binding affinity to PSMA-expressing cells.

[0192] Next, nude mice bearing PC3-PIP tumor xenografts (PSMA-negative tumors) were 86 Y-PSMA-617, 86 Y-PSMA-C12, or 86 PET / CT imaging studies were performed by intravenously injecting Y-PSMA-PhC18 and scanning up to 72 hours after injection. The results are shown in Figures 4A-4C. In Figure 4C, the hydrophobic compound 86 Y-PSMA-PhC18 had long blood circulation and minimal renal clearance. Notably, tumor uptake and retention were 86 Y-PSMA-617 (Figure 4A) and 86 This is a significant improvement compared to Y-PSMA-C12 (Figure 4B).

[0193] next, 86 Y-PSMA-617, 86 Y-PSMA-C12, or 86 Region of interest analysis was performed on PC3-PIP tumor xenografts intravenously injected with Y-PSMA-PhC18 and scanned up to 72 hours after injection. As can be seen in Figure 5, 86 Y-PSMA-PhC18 had a long blood circulation half-life of 11.7 hours and minimal renal clearance. 86 Tumor uptake of Y-PSMA-PhC18 plateaus at 24 hours post-injection (pi).

[0194] next, 86 Y-PSMA-617 and86 In PC3-PIP mice intravenously injected with Y-PSMA-C12, 24 hours after injection, 86 In mice administered Y-PSMA-PhC18, ex vivo biodistribution analysis was performed following the final imaging time point, 72 hours post-injection. As shown in Figure 6, at the biodistribution time point, tumors showed the highest uptake of all analyzed tissues for all three compounds. 86 Y-PSMA-617 is a hydrophilic compound 86 Y-PSMA-617 and 86 Compared with Y-PSMA-C12, it showed 3-fold higher tumor uptake at a much later time point.

[0195] Next, PET / CT imaging studies were performed in nude mice bearing LNCap tumor xenografts with low PSMA expression. 86 Y-PSMA-617, 86 Y-PSMA-C12, or 86 Y-PSMA-PhC18 was injected intravenously and the results of scanning up to 72 hours after injection are shown in Figures 7A-7C. As can be seen in Figure 7C, the more hydrophobic compound 86 Y-PSMA-PhC18 showed prolonged blood circulation and minimized renal clearance compared to the other two compounds. 86 Tumor uptake and retention of Y-PSMA-PhC18 86 This was significantly improved compared with Y-PSMA-617.

[0196] Finally, nude mice bearing LNCap tumor xenografts 86 Y-PSMA-617, 86 Y-PSMA-C12, or 86 Y-PSMA-PhC18 was injected intravenously, and region of interest analysis was performed on PET / CT images scanned up to 72 hours after injection. As can be seen in Figure 8, 86 Y-PSMA-PhC18 had a long blood circulation half-life of 15.1 hours and minimal renal clearance. 86 Tumor uptake of Y-PSMA-PhC18 stagnated at 24 hours after injection, and was significantly higher than that of 24 hours after injection at 72 hours after injection.86 Y-PSMA-617 and 86 This was 5-fold higher than the uptake of Y-PSMA-C12. 86 Y-PSMA-PhC18 demonstrated robust clearance from normal organs.

[0197] Other embodiments and uses of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. The invention is not limited to the particular reagents, formulations, reaction conditions, and the like, illustrated and described herein, but encompasses such modifications thereof as are encompassed by the scope of the following claims.

Claims

1. A compound having the formula 【Chemistry 1】 or a complex, anion or salt thereof, R １ contains a chelating moiety, a is 0 or 1; n is an integer from 12 to 21; R ２ A compound that includes a moiety that targets prostate specific membrane antigen (PSMA).

2. The compound of claim 1 , wherein n is 12.

3. The compound of claim 1 , wherein n is 13.

4. 2. The compound of claim 1, wherein n is 14.

5. The compound of claim 1 , wherein n is 15.

6. The compound of claim 1 , wherein n is 16.

7. The compound of claim 1 , wherein n is 17.

8. The compound of claim 1 , wherein n is 18.

9. The compound of claim 1 , wherein n is 19.

10. 2. The compound of claim 1, wherein n is 20 or 21.

11. The compound of claim 1, wherein the compound is a theranostic agent.

12. 2. The compound of claim 1, wherein the compound is more hydrophobic than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T.

13. The compound of claim 1, wherein the compound is retained in the body of a subject to which it is administered for a longer period of time than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T.

14. 14. The compound of claim 13, wherein the compound remains bound to prostate cancer cells in the body of a subject to which it is administered for a longer period of time than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T.

15. The compound of claim 1, wherein the compound has a higher bioavailability in the body of a subject to which it is administered than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T.

16. 2. The compound of claim 1, wherein the compound is excreted in greater amounts via the liver and in less amount via the kidney from a subject to which it is administered compared to PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T.

17. 2. The compound of claim 1, wherein the compound binds to salivary gland tissue of a subject to which it is administered to a lesser extent than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T.

18. 2. The compound of claim 1, wherein the compound binds to renal tissue of a subject to which it is administered to a lesser extent than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T.

19. The compound of claim 1 , wherein the chelating moiety is chelated to a metal atom.

20. 20. The compound of claim 19, wherein the metal atom is in the form of a metal cation.

21. 21. The compound of claim 20, wherein the chelating moiety is anionic and the compound as a whole is selected to be electrically neutral.

22. 20. The compound of claim 19, wherein the metal atom is a positron or single photon emitting metal isotope, or an alpha, beta, or Auger emitting metal isotope.

23. 23. The compound of claim 22, wherein the metal atom is a positron or single photon emitting metal isotope.

24. 24. The compound of claim 23, wherein the metal isotope is selected from the group consisting of Ga-66, Cu-64, Y-86, Co-55, Zr-89, Sr-83, Mn-52, As-72, Sc-44, Sc-43, Ti-45, Tb-152, La-132, La-133, Ce-134, Ga-67, In-111, or Sm-153, Lu-177, or Tc-99m.

25. 23. The compound of claim 22, wherein the metal atom is an alpha, beta or Auger emitting metal isotope.

26. 26. The compound of claim 25, wherein the metal isotope is selected from the group consisting of Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, Sc-47, Sm-153, Tb-161, Tb-149, Bi-213, Bi-212, or Th-227.

27. The chelating moiety is selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) and derivatives thereof, 1,4,7-triazacyclononane-1,4-diacetic acid (NODA) and derivatives thereof, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and derivatives thereof, 1,4,7,10-tetraazacyclododecane-1,4,7,10-triacetic acid (DOTA) and derivatives thereof, 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) and derivatives thereof, 1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid (DOTAGA) and derivatives thereof, 1,4,8,11-tetraazacyclotetradecane-1,4 2. The compound of claim 1, wherein the compound is selected from the group consisting of 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (TETA) and derivatives thereof, 1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diacetic acid (CB-TE2A) and derivatives thereof, diethylenetriaminepentaacetic acid (DTPA), its diesters and derivatives thereof, 2-cyclohexyldiethylenetriaminepentaacetic acid (CHX-A″-DTPA) and derivatives thereof, deforoxamine (DFO) and derivatives thereof, 1,2-[[6-carboxypyridin-2-yl]methylamino]ethane (H2dedpa) and derivatives thereof, HOPO and derivatives thereof, MACROPA and derivatives thereof, and DADA and derivatives thereof, wherein the DADA has the structure: 【Chemistry 2】

28. The compound of claim 1 , wherein a is 1.

29. The compound of claim 1 , wherein a is 0.

30. R １ 2. The compound of claim 1, wherein is selected from the group consisting of: 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】 【Chemistry 7】 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】

31. The compound of claim 1 , wherein the PSMA targeting moiety comprises a thiol-based PSMA binding motif, a phosphorus-based PSMA binding motif, or a urea-based PSMA binding motif.

32. The compound of claim 31 , wherein the PSMA targeting moiety comprises a urea-based PSMA binding motif.

33. The compound of claim 32, wherein the PSMA targeting moiety comprises a Glu-Urea-Lys PSMA binding motif.

34. R ２ 34. The compound of claim 33, wherein: 【Chemistry 17】

35. The compound of claim 31 , wherein the PSMA targeting moiety comprises a phosphorus-based PSMA binding motif.

36. The compound of claim 35, wherein the PSMA targeting moiety comprises a phosphoramidate-containing PSMA binding motif.

37. R ２ 37. The compound of claim 36, wherein: 【Chemistry 18】

38. 13. A composition comprising a compound of claim 1 and a pharma- ceutically acceptable carrier.

39. The composition of claim 38, wherein the composition does not include an albumin binder.

40. 11. A method for treating a cancer associated with increased PSMA expression in a subject, comprising administering to a subject having cancer an effective amount of a compound of claim 1, said compound comprising a metal atom chelated to said chelating moiety, said metal atom being an alpha, beta, or Auger emitting metal isotope; This successfully treats cancer in the subject.

41. 41. The method of claim 40, wherein the cancer is prostate cancer or breast cancer.

42. 42. The method of claim 41, wherein the cancer is prostate cancer.

43. 41. The method of claim 40, wherein the metal isotope is selected from the group consisting of Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, Sc-47, Sm-153, Tb-161, Tb-149, Bi-213, Bi-212, or Th-227.

44. 41. The method of claim 40, wherein the compound is administered in the absence of an albumen binder.

45. 41. The method of claim 40, wherein the compound is administered by parenteral, intranasal, sublingual, rectal, or transdermal delivery.

46. 46. ​​The method of claim 45, wherein the compound is administered intravenously.

47. 41. The method of claim 40, wherein the subject is a human.

48. 41. The method of claim 40, wherein the compound is retained in the body of the subject to which it is administered for a period of time longer than would be retained if PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T were administered to the subject.

49. 41. The method of claim 40, wherein the compound remains bound to prostate cancer cells in the subject to which it is administered for a period of time longer than the period that PSMA-11, PSMA-617, PSMA-R2, EB-PSMA or PSMA I&T would be bound if administered to the subject.

50. 41. The method of claim 40, wherein the compound has a bioavailability in the body of the subject to which it is administered that is greater than the bioavailability that PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T would have if administered to the subject.

51. The method of claim 40, wherein the compound is excreted hepatically (and to a lesser extent renally) from the subject to which it is administered than would be excreted if PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T were administered to the subject.

52. 41. The method of claim 40, wherein the compound binds to the salivary gland tissue of the subject to which it is administered to a lesser extent than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T would bind if administered to the subject.

53. 41. The method of claim 40, wherein the compound binds to the renal tissue of the subject to which it is administered to a lesser extent than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T binds when administered to the subject.

54. 1. A method for inhibiting the proliferation or growth of malignant cells associated with increased PSMA expression, comprising: contacting one or more malignant cells associated with increased PSMA expression with an effective amount of the compound of claim 1, wherein the compound comprises a metal atom chelated to the chelating moiety, the metal atom being an alpha, beta, or Auger emitting metal isotope; and inhibiting the growth or proliferation of one or more of said malignant cells.

55. 55. The method of claim 54, wherein one or more of the malignant cells is a prostate cell or a breast cell.

56. 56. The method of claim 55, wherein one or more of the malignant cells is a prostate cell.

57. 55. The method of claim 54, wherein the metal isotope is selected from the group consisting of Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, Sc-47, Sm-153, Tb-161, Tb-149, Bi-213, Bi-212, or Th-227.

58. 55. The method of claim 54, wherein the compound is contacted with one or more of the malignant cells in the absence of an albumin binder.

59. 55. The method of claim 54, wherein the method is performed in vivo, ex vivo, or in vitro.

60. 1. A method for detecting or imaging one or more cancer cells associated with increased PSMA expression in a biological sample, comprising: (a) contacting a biological sample with the compound of claim 1, wherein the compound comprises a metal atom chelated to the chelating moiety, the metal atom being a positron or single photon emitting metal isotope, whereby the compound differentially binds to prostate cancer cells within the biological sample; (b) identifying individual cells or regions within the biological sample that emit a signal characteristic of the metal isotope, thereby detecting and / or imaging one or more prostate cancer cells; The method includes:

61. 61. The method of claim 60, wherein the cancer cells are breast cancer cells or prostate cancer cells.

62. 62. The method of claim 61, wherein the cancer cells are prostate cancer cells.

63. 61. The method of claim 60, wherein the metal isotope is selected from the group consisting of Ga-66, Cu-64, Y-86, Co-55, Zr-89, Sr-83, Mn-52, As-72, Sc-44, Sc-43, Ti-45, Tb-152, La-132, La-133, Ce-134, Ga-67, In-111, or Sm-153, Lu-177, or Tc-99m.

64. 61. The method of claim 60, wherein the compound is contacted with the biological sample in the absence of an albumin binding agent.

65. 61. The method of claim 60, wherein the method of identifying individual cells or regions within the biological sample emitting a signal characteristic of the metal isotope is performed by positron emission tomography (PET) imaging, single photon emission computed tomography (SPECT) imaging, or gamma camera planar imaging.

66. 61. The method of claim 60, wherein the biological sample is part or all of a subject.

67. 67. The method of claim 66, wherein the subject is a human.

68. 67. The method of claim 66, wherein the compound is retained in the subject for a period of time greater than the period of time that PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T is retained when contacted with the biological sample.

69. 67. The method of claim 66, wherein the compound remains bound to prostate cancer cells in the subject for a period of time longer than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T would be bound when contacted with the biological sample.

70. 67. The method of claim 66, wherein the compound has a greater bioavailability in the subject than would PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T when contacted with the biological sample.

71. 67. The method of claim 66, wherein the compound is excreted hepatically to a greater extent (and renally to a lesser extent) from the subject than PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T would be excreted when contacted with the biological sample.

72. 67. The method of claim 66, wherein the compound binds to the salivary gland tissue of the subject to an extent less than that of PSMA-11, PSMA-617, PSMA-R2, EB-PSMA, or PSMA I&T when contacted with the biological sample.

73. 67. The method of claim 66, wherein the compound binds to the renal tissue of the subject to an extent less than that of PSMA-11, PSMA-617, PSMA-R2, EB-PSMA or PSMA I&T when contacted with the biological sample.

74. 67. The method of claim 66, wherein the biological sample is obtained from a subject.

75. 75. The method of claim 74, wherein the subject is a human.

76. A method for diagnosing a cancer associated with increased PSMA expression in a subject, comprising performing the method of claim 60, wherein the biological sample is obtained from part or all of the subject, whereby if the cancer cells are detected and / or imaged, the subject is diagnosed with cancer.

77. 77. The method of claim 76, wherein the cancer is breast cancer or prostate cancer.

78. 78. The method of claim 77, wherein the cancer is prostate cancer.

79. 61. A method for monitoring the effectiveness of a cancer treatment in a human subject, wherein the cancer is associated with increased PSMA expression, comprising performing the method of claim 60 on the biological sample at two or more different times, wherein the biological sample is obtained from part or all of the subject, whereby a change in intensity of a signal characteristic of the metal isotope between the two or more different times correlates with the effectiveness of the prostate cancer treatment.

80. 80. The method of claim 79, wherein the cancer is breast cancer or prostate cancer.

81. 81. The method of claim 80, wherein the cancer is prostate cancer.

82. 80. The method of claim 79, wherein the cancer treatment being monitored is chemotherapy or radiation therapy.

83. 61. A method of treating cancer in a subject associated with increased PSMA expression, comprising carrying out the method of claim 60, wherein the biological sample is part or all of the subject, and irradiating identified individual cells or regions within the subject with an external radiation therapy beam; This results in the cancer being treated in the subject.

84. 84. The method of claim 83, wherein the cancer is breast cancer or prostate cancer.

85. 85. The method of claim 84, wherein the cancer is prostate cancer.

86. 1. A method for determining a therapeutic dose of a theranostic agent for treating a cancer associated with increased PSMA expression in a subject, comprising: (a) administering to the subject a detection-enhancing dose of the compound of claim 1, wherein the compound used in the detection-enhancing dose comprises a metal atom chelated to the chelating moiety, the metal atom being a positron or single photon emitting metal isotope; (b) then detecting a signal emanating from one or more of said prostate cancer cells in said subject that is characteristic of said metal isotope of said compound used in said detection-enhancing dose; (c) determining a therapeutic dose of the theranostic agent from the intensity of the signal detected in step (b); The method includes:

87. 87. The method of claim 86, wherein the cancer is breast cancer or prostate cancer.

88. 88. The method of claim 87, wherein the cancer is prostate cancer.

89. 87. The method of claim 86, wherein the metal isotope of the compound used in the detection-enhancing dose is selected from the group consisting of Ga-66, Cu-64, Y-86, Co-55, Zr-89, Sr-83, Mn-52, As-72, Sc-44, Sc-43, Ti-45, Tb-152, La-132, La-133, Ce-134, Ga-67, In-111, or Sm-153, Lu-177, or Tc-99m.

90. 87. The method of claim 86, wherein detecting a signal emanating from one or more of the cancer cells in the subject that is characteristic of the metal isotope of the compound used in the detection-enhancing dose is performed by positron emission tomography (PET) imaging, single photon emission computed tomography (SPECT) imaging, or gamma camera planar imaging.

91. 87. The method of claim 86, further comprising administering to the subject a determined therapeutic dose of the compound of claim 1, wherein the compound used in the therapeutic dose comprises a metal atom chelated to the chelating moiety, and the metal atom is an alpha, beta, or Auger emitting metal isotope.

92. 92. The method of claim 91, wherein the metal isotope of the compound used in the therapeutic dose is selected from the group consisting of Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, Sc-47, Sm-153, Tb-161, Tb-149, Bi-213, Bi-212, or Th-227.

93. 1. A method of treating a cancer associated with increased PSMA expression in a subject, comprising: (a) administering to the subject a detection-enhancing dose of the compound of claim 1, wherein the compound used in the detection-enhancing dose comprises a metal atom chelated to the chelating moiety, the metal atom being a positron or single photon emitting metal isotope; (b) then detecting a signal emanating from one or more of said cancer cells in said subject that is characteristic of said metal isotope of said compound used in said detection-enhancing dose; (c) determining a therapeutic dose of the compound from the intensity of the signal detected in step (b); (d) administering to the subject the therapeutic dose of the compound of claim 1, wherein the compound used in the therapeutic dose comprises a metal atom chelated to the chelating moiety, the metal atom being an alpha, beta, or Auger emitting metal isotope; Whereby said prostate cancer is treated in said subject.

94. 94. The method of claim 93, wherein the cancer is breast cancer or prostate cancer.

95. 95. The method of claim 94, wherein the cancer is prostate cancer.

96. 94. The method of claim 93, wherein the metal isotope of the compound used in the detection-enhancing dose is selected from the group consisting of Ga-66, Cu-64, Y-86, Co-55, Zr-89, Sr-83, Mn-52, As-72, Sc-44, Sc-43, Ti-45, Tb-152, La-132, La-133, Ce-134, Ga-67, In-111, or Sm-153, Lu-177, or Tc-99m.

97. The method of claim 93, wherein detecting a signal emanating from one or more prostate cancer cells in the subject that is characteristic of the metal isotope of the compound used in the detection-enhancing dose is performed by positron emission tomography (PET) imaging, single photon emission computed tomography (SPECT) imaging, or gamma camera planar imaging.

98. 94. The method of claim 93, wherein the metal isotope of the compound used in the therapeutic dose is selected from the group consisting of Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, Sc-47, Sm-153, Tb-161, Tb-149, Bi-213, Bi-212, or Th-227.

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