Potemkin, Roman Strauch, Brigitte Kuwert, Torsten Prante, Olaf Maschauer, Simone Development of <sup>18</sup>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 <sup>18</sup>F-labeled PSMA ligands bearing different <sup>18</sup>F-glycosyl moieties to study the effect on the <i>in vivo</i> clearance behavior of radiotracers in addition to their tumor binding ability. Therefore, we applied click chemistry-based <sup>18</sup>F-fluoroglcosylation using 2-deoxy-2-[<sup>18</sup>F]­fluoroglucosyl azide or 6-deoxy-6-[<sup>18</sup>F]­fluoroglucosyl azide as prosthetic groups for the radiosynthesis of the <sup>18</sup>F-fluoroglycosylated glutamate-urea-lysine-based PSMA inhibitors 2-[<sup>18</sup>F]­FGlc-PSMA ([<sup>18</sup>F]<b>7</b>) and 6-[<sup>18</sup>F]­FGlc-PSMA ([<sup>18</sup>F]<b>8</b>). The PSMA inhibitory potencies were determined by competitive radioligand binding assays using <sup>99m</sup>Tc-MIP-1404 and PSMA-expressing PC-3 PIP cells, revealing moderate PSMA inhibitory potencies for [<sup>18</sup>F]<b>7</b> (IC<sub>50</sub> = 234 nM) and [<sup>18</sup>F]<b>8</b> (IC<sub>50</sub> = 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 [<sup>18</sup>F]<b>7</b> and [<sup>18</sup>F]<b>8</b> were obtained in high radioactivity yields of 19–22% (nondecay-corrected, referred to [<sup>18</sup>F]­fluoride) and with molar activities of 71–136 GBq/μmol. In the biodistribution studies, the uptake levels of [<sup>18</sup>F]<b>7</b> and [<sup>18</sup>F]<b>8</b> 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, [<sup>18</sup>F]<b>7</b> had high uptake in the kidneys, with remarkable retention from 30 to 60 min p.i. (74 to 72%ID/g). In contrast, [<sup>18</sup>F]<b>8</b> 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 <sup>68</sup>Ga-PSMA-11 PET scan of the same mouse, [<sup>18</sup>F]<b>7</b> and [<sup>18</sup>F]<b>8</b> 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 <sup>68</sup>Ga-PSMA-11 and 2-[<sup>18</sup>F]­FGlc-PSMA­([<sup>18</sup>F]<b>7</b>) mainly accumulated in the cortex of the kidneys, whereas 6-[<sup>18</sup>F]­FGlc-PSMA­([<sup>18</sup>F]<b>8</b>) showed a 10-fold lower kidney uptake with accumulation in the inner medulla or pelvis of the kidneys. Overall, the developed 6-fluoroglucosyl derivative [<sup>18</sup>F]<b>8</b>, with its considerably low kidney uptake and fast clearance, demonstrated high uptake in PSMA-positive tumors <i>in vivo.</i> This candidate could, therefore, be valuable for translation into the clinic. kidney distribution pattern;PSMA-expressing PC -3 PIP cells;18 F-glycosyl moieties;positron emission tomography;99 m Tc-MIP -1404;68 Ga-PSMA -11 PET scan;PSMA-negative PC -3 tumor-bearing;uptake values;PC -3 PIP tumors;ID;Renal Clearance Behavior;68 Ga-PSMA -11;kidney uptake;tumor binding ability;30 min p.i;type II transmembrane glycoprotein;IC 50;vivo clearance behavior;60 min p.i;click chemistry-based 18 F-fluoroglcosylation;PSMA-positive PC -3 PIP;small-animal PET studies;radioligand binding assays;18 F-labeled PSMA ligands;prostate-specific membrane antigen;18 F;PSMA-negative PC -3 tumors 2020-02-14
    https://acs.figshare.com/articles/journal_contribution/Development_of_sup_18_sup_F_Fluoroglycosylated_PSMA-Ligands_with_Improved_Renal_Clearance_Behavior/11857986
10.1021/acs.molpharmaceut.9b01179.s001