Synthesis and initial in vitro characterization of a new P2X7R radioligand [18F]IUR-1602. (February 2019)

• Record Type: Journal Article
• Authors: Gao, Mingzhang; Wang, Min; Glick-Wilson, Barbara E.; Meyer, Jill A.; Peters, Jonathan S.; Territo, Paul R.; Green, Mark A.; Hutchins, Gary D.; Zarrinmayeh, Hamideh; Zheng, Qi-Huang
• Is Part Of: Applied radiation and isotopes. Volume 144(2019:Feb.)
• Page Start: 10
• Page End: 18
• Publication Date: 2019-02
• Subjects: [18F]IUR-1602 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-[18F]fluoropropyl)-5-oxopyrrolidine-2-carboxamide) -- Purinergic P2X7 receptor (P2X7R) -- Radiosynthesis -- Competitive binding assay -- Positron emission tomography (PET); Radiology -- Periodicals; Radiation -- Industrial applications -- Periodicals; Nuclear chemistry -- Periodicals; Internet resource; Periodical; 660.298
• DOI: 10.1016/j.apradiso.2018.11.006
• Languages: English
• ISSNs: 0969-8043

Abstract

Abstract: The overexpression of P2X7R is associated with neuroinflammation and plays an important role in various neurodegenerative diseases. The [ 18 F]fluoropropyl derivative of GSK1482160, [ 18 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 [ 18 F]IUR-1602 was synthesized from desmethyl-GSK1482160 with 3-[ 18 F]fluoropropyl tosylate, prepared from propane-1, 3-diyl bis(4-methylbenzenesulfonate) and K[ 18 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 [ 11 C]GSK1482160, and the binding affinity Ki 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 [ 18 F]IUR-1602 compared to [ 11 C]GSK1482160, prevent further in vivo evaluation of [ 18 F]IUR-1602 in animals and human. Highlights: A new P2X7R radioligand [ 18 F]IUR-1602 was synthesized. A 2-step 2-pot fully automated [ 18 F]-radiosynthesis for [ 18 F]IUR-1602 was developed. A semi-preparative RP HPLC-SPE technique was employed in radiosynthesis. Ki value of IUR-1602 was 23.6 ± 0.96 nM.