Synthesis and SAR of 99mTc/Re-labeled small molecule prostate specific membrane antigen inhibitors with novel polar chelates

Lu, Genliang; Maresca, Kevin P.; Hillier, Shawn; Zimmerman, Craig; Eckelman, William C.; Joyal, John L.; Babich, John W.

doi:10.1016/j.bmcl.2012.09.014

Cited by 78 publications

(65 citation statements)

References 24 publications

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“…With regard to radionuclide therapy, MIP1095 and MIP1404 are promising PSMA ligands because these small molecules enable fast tumor targeting, have fast clearance from untargeted organs, and have sufficient residency times in tumor because of ligand-induced cellular internalization (7,11). MIP1404 is of particular interest because its single-amino-acid chelator can be labeled with either 99m Tc for diagnostic applications or 186 Re or 188 Re for therapeutic applications (16,17). Technetium and rhenium are chemically related and have structural and reactive similarities.…”

Section: Discussionmentioning

confidence: 99%

PMPA for Nephroprotection in PSMA-Targeted Radionuclide Therapy of Prostate Cancer

et al. 2015

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Radioactive ligands for the prostate-specific membrane antigen (PSMA) are under development for therapy of metastasized prostate cancer. Since PSMA expression is also found in the kidneys, renal tracer uptake can be dose-limiting. Because kidney kinetics differ from tumor kinetics, serial application of PSMA inhibitors such as 2-(phosphonomethyl)pentanedioic acid (PMPA) may improve the kidney-to-tumor ratio. In this study, we evaluated the effect of PMPA on the biodistribution of 2 promising PSMA ligands. Methods: Human prostate cancer xenografts (LNCaP) were transplanted subcutaneously into mice. After injection of 125 I-MIP1095, a 16-h latency period was allowed for tracer clearance from the blood and renal calices. After baseline scintigraphy, PMPA was injected in doses of 0.2-50 mg/kg (n 5 3 per dose, 5 controls), followed by scans at 2, 4, 6, and 24 h after PMPA injection. Kidney and tumor displacement was determined as a percentage of baseline. A shortened but similar design was used to evaluate the PSMA ligand MIP1404, which contains a chelate for 99m Tc/rhenium. Results: PMPA injection 16 h after MIP1095 translated into a rapid and quantitative relevant displacement of renal activity. Tumor uptake was reduced to a significantly lesser extent in a dose-dependent manner. PMPA doses of 0.2-1 mg/kg appear optimal for sustaining nearly complete tumor uptake while simultaneously achieving near-total blocking of specific renal PSMA binding. The effect was successfully validated with the PSMA ligand MIP1404. Conclusion: PSMA-targeted radionuclide therapy can benefit from serial PMPA comedication by reducing off-target radiation to the kidneys. These data will be used for a first approximation in clinical translation, although in patients an optimization of the dose and time schedule may be necessary.

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Section: Discussionmentioning

confidence: 99%

PMPA for Nephroprotection in PSMA-Targeted Radionuclide Therapy of Prostate Cancer

et al. 2015

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“…1) and radiolabeling with 99m Tc were described previously (25,26). These PSMA inhibitors were synthesized by the attachment of glutamate-urea-lysine and glutamate-urea-glutamate pharmacophore to novel, hydrophilic single-amino-acid chelate (29). The radiolabeling of the study drug precursors MIP-1404 and MIP-1405 with the novel intermediate { 99m Tc(CO) 3 } 1 to form the desired metal complexes was accomplished in 2 steps using standard methodology (25,29).…”

Section: Study Drugsmentioning

confidence: 99%

“…These PSMA inhibitors were synthesized by the attachment of glutamate-urea-lysine and glutamate-urea-glutamate pharmacophore to novel, hydrophilic single-amino-acid chelate (29). The radiolabeling of the study drug precursors MIP-1404 and MIP-1405 with the novel intermediate { 99m Tc(CO) 3 } 1 to form the desired metal complexes was accomplished in 2 steps using standard methodology (25,29). IsoLink kits (Covidien) were used to generate the intermediate { 99m Tc(CO) 3 } 1 in the final preparation of study drugs 99m Tc-MIP-1404 and 99m Tc-MIP-1405 (Fig.…”

Section: Study Drugsmentioning

confidence: 99%

^99mTc-Labeled Small-Molecule Inhibitors of Prostate-Specific Membrane Antigen: Pharmacokinetics and Biodistribution Studies in Healthy Subjects and Patients with Metastatic Prostate Cancer

Vallabhajosula

Nikolopoulou

Babich³

et al. 2014

J Nucl Med

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126

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“…To address this need, investigators at MIP developed a series of 99m Tc-based PSMA ligands and ultimately introduced 2 high-affinity small-molecule PSMA inhibitors, MIP-1404 and MIP-1405 (Supplemental Fig. 1), into the clinical setting in 2010 (34,45). Although both 99m Tc agents are based on the glutamateurea amino acid core and have similar PSMA binding affinities (34), significantly different pharmacokinetic parameters were observed in human studies; these were most likely due to modest structural differences affecting hydrophobicity and protein binding (46).…”

Section: Psma Ligand Spect Imagingmentioning

confidence: 99%

The Rise of PSMA Ligands for Diagnosis and Therapy of Prostate Cancer

et al. 2016

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Synthesis and SAR of 99mTc/Re-labeled small molecule prostate specific membrane antigen inhibitors with novel polar chelates

Cited by 78 publications

References 24 publications

PMPA for Nephroprotection in PSMA-Targeted Radionuclide Therapy of Prostate Cancer

PMPA for Nephroprotection in PSMA-Targeted Radionuclide Therapy of Prostate Cancer

^99mTc-Labeled Small-Molecule Inhibitors of Prostate-Specific Membrane Antigen: Pharmacokinetics and Biodistribution Studies in Healthy Subjects and Patients with Metastatic Prostate Cancer

The Rise of PSMA Ligands for Diagnosis and Therapy of Prostate Cancer

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