Clemens Kratochwil1, Frederik L Giesel2, Karin Leotta3, Matthias Eder4, Torsten Hoppe-Tich5, Hagop Youssoufian6, Klaus Kopka4, John W Babich7, Uwe Haberkorn2. 1. Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany clemens.kratochwil@med.uni-heidelberg.de. 2. Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (dkfz), Heidelberg, Germany. 3. Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (dkfz), Heidelberg, Germany. 4. Division of Radiopharmaceutical Chemistry, German Cancer Research Center (dkfz), Heidelberg, Germany. 5. Pharmacy Department, University Hospital of Heidelberg, Heidelberg, Germany. 6. Progenics Pharmaceuticals Inc., Tarrytown, New York; and. 7. Department of Radiopharmacy, Weill Cornell Medical College, New York, New York.
Abstract
UNLABELLED: 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 = 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.
UNLABELLED: 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:Humanprostate 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 = 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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