Abstract
Radioactive ligands for the prostate specific membrane antigen (PSMA) are under development for therapy of metastasized prostate cancer (PCa). Since PSMA expression is also found in the kidneys, renal tracer uptake can be dose limiting. As kidney kinetics differs from tumor kinetics, serial application of PSMA-inhibitors such as 2-(phosphonomethyl)pentanedioic acid (PMPA) could improve the kidney-to-tumor ratio. In this study, we evaluate the effect of PMPA on the biodistribution of two promising PSMA-ligands. Methods: Human PCa xenografts (LNCaP) were transplanted s.c. into mice. After injection of 125I-MIP1095, a 16h latency period was given to allow 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 2h, 4h, 6h and 24h post PMPA injection. Kidney and tumor displacement was determined as percentage of baseline. A shortened but similar design was used to evaluate the PSMA ligand MIP1404 which contains a chelate for 99mTc/Re. Results: PMPA injection 16h after MIP1095 translated into a rapid and quantitative relevant displacement of renal activity. The tumor uptake was reduced to a significant lesser extent also in a dose dependent manner. PMPA doses of 0.2-1mg/kg appear optimal to sustain 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 co-medication by reducing off-target radiation to 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.
- Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.