Synthesis and preliminary biological evaluation of a novel P2X7R radioligand [ 18 F]IUR-1601.

The reference standard IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from tert-butyl (S)-5-oxopyrrolidine-2-carboxylate, fluoroethylbromide, and 2-chloro-3-(trifluoromethyl)benzylamine with overall chemical yield 12% in three steps. The target tracer [18 F]IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-[18 F]fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from desmethyl-GSK1482160 with 2-[18 F]fluoroethyl tosylate, prepared from 1,2-ethylene glycol-bis-tosylate and K[18 F]F/Kryptofix2.2.2, in two steps and isolated by HPLC combined with SPE in 1-3% 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-1601 in comparison with GSK1482160 was determined by a radioligand competitive binding assay using [11 C]GSK1482160, and the binding affinity Ki values for IUR-1601 and GSK1482160 are 4.31 and 5.14 nM, respectively.