PURPOSE: Prostate-specific membrane antigen (PSMA) radioligand therapy is a promising treatment for metastatic castration-resistant prostate cancer (mCRPC). Several beta or alpha particle-emitting radionuclide-conjugated small molecules have shown efficacy in late-stage mCRPC and one, [[177Lu]Lu]Lu-PSMA-617, is FDA approved. In addition to tumor upregulation, PSMA is also expressed in kidneys and salivary glands where specific uptake can cause dose-limiting xerostomia and potential for nephrotoxicity. The PSMA inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) can prevent kidney uptake in mice, but also blocks tumor uptake, precluding its clinical utility. Preferential delivery of 2-PMPA to non-malignant tissues could improve the therapeutic window of PSMA radioligand therapy. METHODS: A tris(isopropoxycarbonyloxymethyl) (TrisPOC) prodrug of 2-PMPA, JHU-2545, was synthesized to enhance 2-PMPA delivery to non-malignant tissues. Mouse pharmacokinetic experiments were conducted to compare JHU-2545-mediated delivery of 2-PMPA to plasma, kidney, salivary glands, and C4-2 prostate tumor xenograft. Imaging studies were conducted in rats and mice to measure uptake of PSMA PET tracers in kidney, salivary glands, and prostate tumor xenografts with and without JHU-2545 pre-treatment. RESULTS: JHU-2545 resulted in approximately 3- and 53-fold greater exposure of 2-PMPA in rodent salivary glands (18.0 ± 0.97 h*nmol/g) and kidneys (359 ± 4.16 h*nmol/g) versus prostate tumor xenograft (6.79 ± 0.19 h*nmol/g). JHU-2545 also blocked rodent kidneys and salivary glands uptake of the PSMA PET tracers [68Ga]Ga-PSMA-11 and [18 F]F-DCFPyL by up to 85% with little effect on tumor. CONCLUSIONS: JHU-2545 pre-treatment may enable greater cumulative administered doses of PSMA radioligand therapy, possibly improving safety and efficacy.

Department of Neurology Johns Hopkins School of Medicine Baltimore MD 21205 USA

Department of Nuclear Medicine University Hospital Heidelberg Heidelberg Germany

Departments of Medicine Johns Hopkins School of Medicine Baltimore MD 21205 USA

Departments of Neuroscience Johns Hopkins School of Medicine Baltimore MD 21205 USA

Departments of Oncology Johns Hopkins School of Medicine Baltimore MD 21205 USA

Departments of Psychiatry Johns Hopkins School of Medicine Baltimore MD 21205 USA

Depatment of Radiology and Radiological Science Johns Hopkins School of Medicine Baltimore MD 21205 USA

Depatment of Radiology Washington University School of Medicine Saint Louis MO 63110 USA

Division of Radiopharmaceutical Sciences and MI Department of Radiology Weill Cornell Medicine New York NY USA

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic v v i Prague 166 10 Czech Republic

Johns Hopkins Drug Discovery 855 North Wolfe Street Baltimore Maryland 21205 USA

Johns Hopkins Drug Discovery Johns Hopkins School of Medicine Baltimore MD 21205 USA

Translational Laboratory Shared Service University of Maryland School of Medicine 655 West Baltimore Street Baltimore MD 21201 USA

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