Development of F-Fluoroglycosylated PSMA-Ligands with Improved Renal Clearance Behavior.

The prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein that is highly expressed in the malignant human prostate epithelium. Therefore, PSMA has emerged as a very attractive target for developing radiopharmaceuticals for the diagnosis, e.g., by positron emission tomography (PET) imaging, and radiotherapy of prostate cancer. The aim of this study was to develop F-labeled PSMA ligands bearing different F-glycosyl moieties to study the effect on the clearance behavior of radiotracers in addition to their tumor binding ability. Therefore, we applied click chemistry-based F-fluoroglcosylation using 2-deoxy-2-[F]fluoroglucosyl azide or 6-deoxy-6-[F]fluoroglucosyl azide as prosthetic groups for the radiosynthesis of the F-fluoroglycosylated glutamate-urea-lysine-based PSMA inhibitors 2-[F]FGlc-PSMA ([F]) and 6-[F]FGlc-PSMA ([F]). The PSMA inhibitory potencies were determined by competitive radioligand binding assays using Tc-MIP-1404 and PSMA-expressing PC-3 PIP cells, revealing moderate PSMA inhibitory potencies for [F] (IC = 234 nM) and [F] (IC = 59 nM). Biodistribution and small-animal PET studies were performed using PSMA-positive PC-3 PIP and PSMA-negative PC-3 tumor-bearing nude mice. PSMA inhibitors [F] and [F] were obtained in high radioactivity yields of 19-22% (nondecay-corrected, referred to [F]fluoride) and with molar activities of 71-136 GBq/μmol. In the biodistribution studies, the uptake levels of [F] and [F] in PC-3 PIP tumors were 13 ± 3%ID/g and 6 ± 5%ID/g at 60 min p.i., respectively. PSMA-negative PC-3 tumors and all other tissues had negligible low uptake values. Interestingly, [F] had high uptake in the kidneys, with remarkable retention from 30 to 60 min p.i. (74 to 72%ID/g). In contrast, [F] revealed a low uptake of 7.5%ID/g in the kidneys at 30 min p.i. and was rapidly cleared through the kidney (0.9%ID/g at 120 min p.i.). In direct comparison to a Ga-PSMA-11 PET scan of the same mouse, [F] and [F] showed 2- to 3-fold higher uptake values in PC-3 PIP tumors. Both radiotracers were solely cleared via the kidneys and not via the hepatobiliary pathway. The regional kidney distribution pattern of the tracers in the kidneys revealed that Ga-PSMA-11 and 2-[F]FGlc-PSMA([F]) mainly accumulated in the cortex of the kidneys, whereas 6-[F]FGlc-PSMA([F]) showed a 10-fold lower kidney uptake with accumulation in the inner medulla or pelvis of the kidneys. Overall, the developed 6-fluoroglucosyl derivative [F], with its considerably low kidney uptake and fast clearance, demonstrated high uptake in PSMA-positive tumors This candidate could, therefore, be valuable for translation into the clinic.