title: PMPA for nephroprotection in PSMA-targeted radionuclide therapy of prostate cancer.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany clemens.kratochwil@med.uni-heidelberg.de.
authors.forename: Clemens
authors.initials: C
authors.lastname: Kratochwil
authors.affiliation: Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (dkfz), Heidelberg, Germany.
authors.forename: Frederik L
authors.initials: FL
authors.lastname: Giesel
authors.affiliation: Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (dkfz), Heidelberg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Leotta
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (dkfz), Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eder
authors.affiliation: Pharmacy Department, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Hoppe-Tich
authors.affiliation: Progenics Pharmaceuticals Inc., Tarrytown, New York; and.
authors.forename: Hagop
authors.initials: H
authors.lastname: Youssoufian
authors.affiliation: Division of Radiopharmaceutical Chemistry, German Cancer Research Center (dkfz), Heidelberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Kopka
authors.affiliation: Department of Radiopharmacy, Weill Cornell Medical College, New York, New York.
authors.forename: John W
authors.initials: JW
authors.lastname: Babich
authors.affiliation: Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (dkfz), Heidelberg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Haberkorn
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism*; D005971:Glutamates; D006801:Humans; D007668:Kidney / Q000000981:diagnostic imaging; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000493:pharmacokinetics; D015609:Organotechnetium Compounds / Q000737:chemistry; D011877:Radionuclide Imaging; D013667:Technetium / Q000737:chemistry; D013997:Time Factors; D014508:Urea / Q000031:analogs & derivatives
chemical_list: C544834:2-(3-(1-carboxy-5-(3-(4-iodobphenyl)ureido)pentyl)ureido)pentanedioic acid; C402107:2-(phosphonomethyl)pentanedioic acid; D000954:Antigens, Surface; D005971:Glutamates; D008024:Ligands; D009943:Organophosphorus Compounds; D015609:Organotechnetium Compounds; C000595576:technetium 99m 1-(1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-2-((1-(2-(bis(carboxymethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)methyl)-9,14-dioxo-2,8,13,15-tetraazaoctadecane-7,12,16,18-tetracarboxylic acid); D013667:Technetium; D014508:Urea; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: PMPA; PSMA; nephroprotection; prostate cancer; radionuclide therapy