Albumin-Binding PSMA Radioligands: Impact of Minimal Structural Changes on the Tissue Distribution Profile.

Luisa M Deberle,Viviane J Tschan,Cristina Müller,Roger Schibli,Fan Sozzi-Guo,Francesca Borgna,Peter Bernhardt

doi:10.3390/molecules25112542

Abstract

The concept of using ibuprofen as an albumin-binding entity was recently demonstrated by the development of [177Lu]Lu-Ibu-PSMA-01. In the present study, we designed a novel ibuprofen-containing radioligand (Ibu-PSMA-02) with subtle structural changes regarding the linker entity in order to investigate a potential impact on the in vitro and in vivo properties. Ibu-PSMA-02 was prepared using solid-phase synthesis techniques and labeled with lutetium-177. [177Lu]Lu-Ibu-PSMA-02 was evaluated in vitro with regard to its plasma protein-binding properties, PSMA affinity and uptake into PSMA-expressing PC-3 PIP tumor cells. The tissue distribution profile of [177Lu]Lu-Ibu-PSMA-02 was assessed in tumor-bearing mice and dose estimations were performed. The in vitro characteristics of [177Lu]Lu-Ibu-PSMA-02 were similar to those previously obtained for [177Lu]Lu-Ibu-PSMA-01 with respect to plasma protein-binding, PSMA affinity and tumor cell uptake. The in vivo studies revealed, however, an unprecedentedly high uptake of [177Lu]Lu-Ibu-PSMA-02 in PC-3 PIP tumors, resulting in an increased absorbed tumor dose of 7.7 Gy/MBq as compared to 5.1 Gy/MBq calculated for [177Lu]Lu-Ibu-PSMA-01. As a consequence of the high tumor accumulation, [177Lu]Lu-Ibu-PSMA-02 showed higher tumor-to-background ratios than [177Lu]Lu-Ibu-PSMA-01. This study exemplified that smallest structural changes in the linker entity of PSMA radioligands may have a significant impact on their pharmacokinetic profiles and, thus, may be applied as a means for ligand design optimization.

Highlights

The prostate-specific membrane antigen (PSMA) was found to be overexpressed in the majority of prostate cancer cases [1,2] and is, a promising target for radionuclide therapy of metastatic castration-resistant prostate cancer [3,4,5]
This study exemplified that smallest structural changes in the linker entity of PSMA radioligands may have a significant impact on their pharmacokinetic profiles and, may be applied as a means for ligand design optimization
A wide variety of PSMA-targeting radioligands were developed in recent years, among them conjugates for labeling with a variety of therapeutic radionuclides [6,7]. [177 Lu]Lu-PSMA-617 is the currently best-known PSMA radioligand for therapeutic application and employed in a Phase III clinical study (VISION, NCT03511664) [8]

Summary

Introduction

The prostate-specific membrane antigen (PSMA) was found to be overexpressed in the majority of prostate cancer cases [1,2] and is, a promising target for radionuclide therapy of metastatic castration-resistant prostate cancer (mCRPC) [3,4,5]. A wide variety of PSMA-targeting radioligands were developed in recent years, among them conjugates for labeling with a variety of therapeutic radionuclides [6,7]. PSMA-targeting radioligands modified with these entities showed enhanced blood circulation in comparison to [177 Lu]Lu-PSMA-617 and, as a consequence, considerably increased accumulation in the tumor tissue, which correlated with better therapeutic outcomes in preclinical settings [10,11,12]. The most widely used albumin binder for the modification of PSMA-targeting radioligands is the p-iodophenyl entity, previously discovered to bind with high affinity to serum albumin [13]. Another successfully applied albumin-binding entity is the azo dye

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