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 ¹⁸F-labeled PSMA ligands bearing different ¹⁸F-glycosyl moieties to study the effect on the in vivo clearance behavior of radiotracers in addition to their tumor binding ability. Therefore, we applied click chemistry-based ¹⁸F-fluoroglcosylation using 2-deoxy-2-[¹⁸F]fluoroglucosyl azide or 6-deoxy-6-[¹⁸F]fluoroglucosyl azide as prosthetic groups for the radiosynthesis of the ¹⁸F-fluoroglycosylated glutamate-urea-lysine-based PSMA inhibitors 2-[¹⁸F]FGlc-PSMA ([¹⁸F]7) and 6-[¹⁸F]FGlc-PSMA ([¹⁸F]8). The PSMA inhibitory potencies were determined by competitive radioligand binding assays using ^99mTc-MIP-1404 and PSMA-expressing PC-3 PIP cells, revealing moderate PSMA inhibitory potencies for [¹⁸F]7 (IC₅₀ = 234 nM) and [¹⁸F]8 (IC₅₀ = 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 [¹⁸F]7 and [¹⁸F]8 were obtained in high radioactivity yields of 19-22% (nondecay-corrected, referred to [¹⁸F]fluoride) and with molar activities of 71-136 GBq/μmol. In the biodistribution studies, the uptake levels of [¹⁸F]7 and [¹⁸F]8 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, [¹⁸F]7 had high uptake in the kidneys, with remarkable retention from 30 to 60 min p.i. (74 to 72%ID/g). In contrast, [¹⁸F]8 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 ⁶⁸Ga-PSMA-11 PET scan of the same mouse, [¹⁸F]7 and [¹⁸F]8 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 ⁶⁸Ga-PSMA-11 and 2-[¹⁸F]FGlc-PSMA([¹⁸F]7) mainly accumulated in the cortex of the kidneys, whereas 6-[¹⁸F]FGlc-PSMA([¹⁸F]8) showed a 10-fold lower kidney uptake with accumulation in the inner medulla or pelvis of the kidneys. Overall, the developed 6-fluoroglucosyl derivative [¹⁸F]8, with its considerably low kidney uptake and fast clearance, demonstrated high uptake in PSMA-positive tumors in vivo. This candidate could, therefore, be valuable for translation into the clinic.

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