Radiohalogenated Prostate-Specific Membrane Antigen (PSMA)-Based Ureas as Imaging Agents for Prostate Cancer

Chen, Ying; Foss, Catherine A.; Byun, Youngjoo; Nimmagadda, Sridhar; Pullambhatla, Mrudula; Fox, James J.; Castanares, Mark; Lupold, Shawn E.; Babich, John W.; Mease, Ronnie C.; Pomper, Martin G.

doi:10.1021/jm801055h

Cited by 177 publications

(225 citation statements)

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“…Indeed, several αPSMA monoclonal antibodies have been used as vehicles for the targeted delivery of cytotoxic agents including radioactive isotopes, small molecules, and protein toxins (4,20,21). A series of small molecule PSMA inhibitors with high affinity (in the low nanomolar range) and selectivity also have been explored for selective lysis or imaging of PSMA + prostate cancer cells (18,22,23). Because of their small size, such small molecule-based targeting agents (peptides, vitamins, and substrate analogs) have better tumor penetration than antibodies (24).…”

Section: Resultsmentioning

confidence: 99%

Bispecific small molecule–antibody conjugate targeting prostate cancer

Kim

Axup

Lawson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Bispecific antibodies, which simultaneously target CD3 on T cells and tumor-associated antigens to recruit cytotoxic T cells to cancer cells, are a promising new approach to the treatment of hormone-refractory prostate cancer. Here we report a site-specific, semisynthetic method for the production of bispecific antibodylike therapeutics in which a derivative of the prostate-specific membrane antigen-binding small molecule DUPA was selectively conjugated to a mutant αCD3 Fab containing the unnatural amino acid, p-acetylphenylalanine, at a defined site. Homogeneous conjugates were generated in excellent yields and had good solubility. The efficacy of the conjugate was optimized by modifying the linker structure, relative binding orientation, and stoichiometry of the ligand. The optimized conjugate showed potent and selective in vitro activity (EC 50 ∼100 pM), good serum half-life, and potent in vivo activity in prophylactic and treatment xenograft mouse models. This semisynthetic approach is likely to be applicable to the generation of additional bispecific agents using drug-like ligands selective for other cell-surface receptors.antibody engineering | immunotherapy

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Section: Resultsmentioning

confidence: 99%

Bispecific small molecule–antibody conjugate targeting prostate cancer

Kim

Axup

Lawson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…1) were prepared by the method of Chen et al and Maresca et al, respectively (18,19). Stannane 3 was prepared as previously described (18).…”

Section: Chemistrymentioning

confidence: 99%

“…1) were prepared by the method of Chen et al and Maresca et al, respectively (18,19). Stannane 3 was prepared as previously described (18). Details regarding the synthesis of 4 and radiochemistry are presented in the supplemental materials (available at http://jnm.snmjournals.org).…”

Section: Chemistrymentioning

confidence: 99%

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(2S)-2-(3-(1-Carboxy-5-(4-²¹¹At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy

et al. 2016

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Alpha-particle emitters have a high linear energy transfer and short range, offering the potential for treating micrometastases while sparing normal tissues. We developed a urea-based, 211 At-labeled small molecule targeting prostate-specific membrane antigen (PSMA) for the treatment of micrometastases due to prostate cancer (PC). Methods: PSMA-targeted (2S)-2-(3-(1-carboxy-5-(4-211 At-astatobenzamido) pentyl)ureido)-pentanedioic acid ( 211 At-6) was synthesized. Cellular uptake and clonogenic survival were tested in PSMA-positive (PSMA1) PC3 PIP and PSMA-negative (PSMA−) PC3 flu human PC cells after 211 At-6 treatment. The antitumor efficacy of 211 At-6 was evaluated in mice bearing PSMA1 PC3 PIP and PSMA-PC3 flu flank xenografts at a 740-kBq dose and in mice bearing PSMA1, luciferase-expressing PC3-ML micrometastases. Biodistribution was determined in mice bearing PSMA1 PC3 PIP and PSMA-PC3 flu flank xenografts. Suborgan distribution was evaluated using α-camera images, and microscale dosimetry was modeled. Longterm toxicity was assessed in mice for 12 mo. Results: 211 At-6 treatment resulted in PSMA-specific cellular uptake and decreased clonogenic survival in PSMA1 PC3 PIP cells and caused significant tumor growth delay in PSMA1 PC3 PIP flank tumors. Significantly improved survival was achieved in the newly developed PSMA1 micrometastatic PC model. Biodistribution showed uptake of 211 At-6 in PSMA1 PC3 PIP tumors and in kidneys. Microscale kidney dosimetry based on α-camera images and a nephron model revealed hot spots in the proximal renal tubules. Long-term toxicity studies confirmed that the dose-limiting toxicity was late radiation nephropathy. Conclusion: PSMA-targeted 211 At-6 α-particle radiotherapy yielded significantly improved survival in mice bearing PC micrometastases after systemic administration. 211 At-6 also showed uptake in renal proximal tubules resulting in late nephrotoxicity, highlighting the importance of long-term toxicity studies and microscale dosimetry.

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“…We have focused on 18 F-labeled radiotracers for PSMAtargeted imaging (8)(9)(10)(11)(12) given the improved prospects for centralized radiotracer production and the potential for better image quality (13). We developed 2-(3-(1carboxy-5-(6-[ 18 F]fluoro-pyridine-3-carbonyl)amino]-pentyl)-ureido)-pentanedioic acid ( 18 F-DCFPyL) as a second-generation fluorinated PSMA-targeted PET radiotracer to improve the tissue distribution of our first-generation agent (12,14).…”

mentioning

confidence: 99%

Semiquantitative Parameters in PSMA-Targeted PET Imaging with ¹⁸F-DCFPyL: Variability in Normal-Organ Uptake

Rowe

Leal

et al. 2016

J Nucl Med

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18 F-DCFPyL is a small-molecule inhibitor of the prostate-specific membrane antigen that has shown promise for evaluation of primary and metastatic prostate cancer using PET. Measuring the variability in normal-organ uptake of 18 F-DCFPyL is necessary to understand its biodistribution, aid image interpretation, judge the reliability of scan quantification, and provide a basis for therapeutic monitoring. Methods: Sixty-five consecutive 18 F-DCFPyL PET/CT scans from 64 patients with a history of prostate cancer were analyzed. Volumes of interest were defined for the lacrimal glands, major salivary glands, liver, spleen, and both kidneys. The mean SUV normalized to body mass or to lean body mass (SUL) was calculated for each volume of interest. The average SUV across all scans, the SD, and the coefficient of variation (COV) for each organ were calculated. The same parameters were also derived for a 3-cm sphere drawn in the center of the right lobe of the liver. Results: The average SUV mean for all selected organs measured was 6.6 6 1.8 for the right lacrimal gland, 6.4 6 1.8 for the left lacrimal gland, 9.1 6 2.0 for the right parotid gland, 9.0 6 2.1 for the left parotid gland, 9.6 6 2.3 for the right submandibular gland, 9.4 6 2.2 for the left submandibular gland, 5.0 6 0.7 for the whole liver, 5.1 6 0.7 for a 3-cm sphere in the liver, 4.0 6 1.5 for the spleen, 20.1 6 4.6 for the right kidney, and 19.4 6 4.5 for the left kidney. SUL mean was lower overall, although demonstrating similar trends. The COV of SUV mean and SUL mean was lower in the liver (13.8% and 14.5%, respectively) than in any other organ and was less than the comparable COV for 18 F-FDG PET. The COV of SUV mean and SUL mean in the 3-cm sphere in the liver was also low and similar to the variability in the whole liver (14.2% and 14.7%, respectively). Conclusion: 18 F-DCFPyL uptake in normal liver demonstrates less variability than in other 18 F-DCFPyL-avid organs, and its variability is less than the reported variability of 18 F-FDG in liver. Variability was slightly less for SUV mean than for SUL mean , suggesting that SUV mean may be the preferable parameter for quantification of images obtained with 18 F-DCFPyL.

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Radiohalogenated Prostate-Specific Membrane Antigen (PSMA)-Based Ureas as Imaging Agents for Prostate Cancer

Abstract: To extend our development of new imaging agents targeting the prostate-specific membrane antigen (PSMA), we have used the versatile intermediate 2-

Cited by 177 publications

References 44 publications

Bispecific small molecule–antibody conjugate targeting prostate cancer

Bispecific small molecule–antibody conjugate targeting prostate cancer

(2S)-2-(3-(1-Carboxy-5-(4-²¹¹At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy

Semiquantitative Parameters in PSMA-Targeted PET Imaging with ¹⁸F-DCFPyL: Variability in Normal-Organ Uptake

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Radiohalogenated Prostate-Specific Membrane Antigen (PSMA)-Based Ureas as Imaging Agents for Prostate Cancer

Abstract: To extend our development of new imaging agents targeting the prostate-specific membrane antigen (PSMA), we have used the versatile intermediate 2-

Cited by 177 publications

References 44 publications

Bispecific small molecule–antibody conjugate targeting prostate cancer

Bispecific small molecule–antibody conjugate targeting prostate cancer

(2S)-2-(3-(1-Carboxy-5-(4-211At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy

Semiquantitative Parameters in PSMA-Targeted PET Imaging with 18F-DCFPyL: Variability in Normal-Organ Uptake

Contact Info

Product

Resources

About

(2S)-2-(3-(1-Carboxy-5-(4-²¹¹At-Astatobenzamido)Pentyl)Ureido)-Pentanedioic Acid for PSMA-Targeted α-Particle Radiopharmaceutical Therapy

Semiquantitative Parameters in PSMA-Targeted PET Imaging with ¹⁸F-DCFPyL: Variability in Normal-Organ Uptake