PMPA for Nephroprotection in PSMA-Targeted Radionuclide Therapy of Prostate Cancer
Open accessAbstract
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.
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Small-molecule PSMA inhibitors such as PMPA can displace noninternalized PSMA ligand 16 hours after PSMA RLT in preclinical models.
“it has been shown that small-molecule PSMA inhibitors such as 2-(phosphonomethyl) pentanedioic acid (PMPA) can displace noninternalized PSMA ligand 16 h after PSMA RLT in preclinical models ( 67 ).”
From Normal-Tissue Tolerance to Radiopharmaceutical Therapies, the Knowns and the Unknowns (2021) · cites this paper as [67]
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References 34 · Cited by 117
Research works printed but not linked: 1
- Vallabhajosula S, Kuji I, Hamacher KA, et al. Pharmacokinetics and biodistri- bution of 111 In and 177 Lu labeled J591 antibody specific to prostate specific membrane antigen: prediction of 90 Y-J591 radiation dosimetry based on 111 In or 177 Lu. J Nucl Med. 2005;46:634-641.
- Authors
- Kratochwil, C., Giesel, F. L., Leotta, K., Eder, M., Hoppe-Tich, T., Youssoufian, H., Kopka, K., Babich, J. W., & Haberkorn, U.
- Affiliations
- University Hospital Heidelberg (DE)
- German Cancer Research Center (DE)
- Progenics Pharmaceuticals (United States) (US)
- Weill Cornell Medicine (US)
- ORCID
- Venue
- Journal of Nuclear Medicine
- Publisher
- Society of Nuclear Medicine
- Published
- 2015-01-22
- Volume
- 56
- Issue
- 2
- Pages
- 293-298
- ISSN
- 0161-5505 (ISSN-L)
- 2159-662X
- OpenAlex
- W2160881737
- Cited by
- 117
- References
- 34
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 6 · 2023: 10 · 2022: 8 · 2021: 16 · 2020: 12 · 2019: 18 · 2018: 13 · 2017: 12 · 2016: 10 · 2015: 3
- FWCI
- 10.25
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Nuclear Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
- Keywords
- PMPA, prostate-specific membrane antigen, PSMA radioligand therapy, prostate cancer, renal protection, tissue distribution, LNCaP xenografts
- MeSH terms
- Animals, Antigens, Surface, Glutamates, Humans, Kidney, Ligands, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Organophosphorus Compounds, Radionuclide Imaging, Technetium, Time Factors, Urea, Organotechnetium Compounds, Glutamate Carboxypeptidase II, Mice
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