Synthesis and initial in vitro characterization of a new P2X7R radioligand [F]IUR-1602.

The overexpression of P2X7R is associated with neuroinflammation and plays an important role in various neurodegenerative diseases. The [F]fluoropropyl derivative of GSK1482160, [F]IUR-1602, has been first prepared and examined as a new potential P2X7R radioligand. The reference standard IUR-1602 was synthesized from tert-butyl (S)-5-oxopyrrolidine-2-carboxylate, fluoropropylbromide, and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 13% in three steps. The target tracer [F]IUR-1602 was synthesized from desmethyl-GSK1482160 with 3-[F]fluoropropyl tosylate, prepared from propane-1,3-diyl bis(4-methylbenzenesulfonate) and K[F]F/Kryptofix2.2.2, in two steps and isolated by HPLC combined with SPE in 2-7% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity at end of bombardment (EOB) was 74-370 GBq/μmol. The potency of IUR-1602 in comparison with GSK1482160 was determined by a radioligand competitive binding assay using [C]GSK1482160, and the binding affinity K values for IUR-1602 and GSK1482160 are 23.6 and 3.07 nM, respectively. The initial in vitro evaluation results, 8-fold less potency of [F]IUR-1602 compared to [C]GSK1482160, prevent further in vivo evaluation of [F]IUR-1602 in animals and human.