JHU-2545 preferentially shields salivary glands and kidneys during PSMA-targeted imaging

Michael T Nedelcovych; Ranjeet P Dash; Ying Wu; Eun Yong Choi; Rena S Lapidus; Pavel Majer; Andrej Jančařík; Diane Abou; Marie-France Penet; Anastasia Nikolopoulou; Alex Amor-Coarasa; John Babich; Daniel L Thorek; Rana Rais; Clemens Kratochwil; Barbara S Slusher

doi:10.1007/s00259-024-07044-7

JHU-2545 preferentially shields salivary glands and kidneys during PSMA-targeted imaging

Eur J Nucl Med Mol Imaging. 2025 Jan 2. doi: 10.1007/s00259-024-07044-7. Online ahead of print.

Authors

Michael T Nedelcovych^{1

2

3}, Ranjeet P Dash^{4

5}, Ying Wu⁴, Eun Yong Choi⁶, Rena S Lapidus⁶, Pavel Majer⁷, Andrej Jančařík⁷, Diane Abou⁸, Marie-France Penet^{9

10}, Anastasia Nikolopoulou¹¹, Alex Amor-Coarasa¹¹, John Babich¹¹, Daniel L Thorek⁸, Rana Rais^{4

5}, Clemens Kratochwil¹², Barbara S Slusher^{13

14

15

16

17

18

19}

Affiliations

¹ Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. [email protected].
² Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. [email protected].
³ Johns Hopkins Drug Discovery, 855 North Wolfe Street, Baltimore, Maryland, 21205, USA. [email protected].
⁴ Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
⁵ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
⁶ Translational Laboratory Shared Service, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD, 21201, USA.
⁷ Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic v.v.i, Prague, 166 10, Czech Republic.
⁸ Depatment of Radiology, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
⁹ Departments of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
¹⁰ Depatment of Radiology and Radiological Science, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA.
¹¹ Division of Radiopharmaceutical Sciences and MI(3), Department of Radiology, Weill Cornell Medicine, New York, NY, USA.
¹² Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany.
¹³ Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. [email protected].
¹⁴ Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. [email protected].
¹⁵ Departments of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. [email protected].
¹⁶ Departments of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. [email protected].
¹⁷ Departments of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. [email protected].
¹⁸ Departments of Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. [email protected].
¹⁹ Johns Hopkins Drug Discovery, 855 North Wolfe Street, Baltimore, Maryland, 21205, USA. [email protected].

PMID: 39743616
DOI: 10.1007/s00259-024-07044-7

Abstract

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.

Keywords: Kidneys; PSMA; Prostate cancer; Radioligand therapy; Salivary glands.

Abstract

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