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

• Published in: The Journal of nuclear medicine (1978) Vol. 59; p. 181
• Main Authors: Gao, Mingzhang, Wang, Min, Glick-Wilson, Barbara, Meyer, Jill, Peters, Jonathan, Territo, Paul, Green, Mark, Hutchins, Gary, Zarrinmayeh, Hamideh, Zheng, Qi-Huang
• Format: Journal Article
• Language: English
• Published: New York Society of Nuclear Medicine 01.05.2018
• Subjects: Affinity; Automation; Binding; Chemical synthesis; Evaluation; Fluorine isotopes; High temperature; Imaging; Inflammation; Ligands; Medical imaging; Molecular biology; Optimization; Organic chemistry; Positron emission; Positron emission tomography; Precursors; Pyroglutamic acid; Radioactive materials; Radiochemistry; Radiology; Target recognition; Temperature requirements; Tomography
• ISSN: 0161-5505; 1535-5667

Objectives: The purinergic receptor subtype 7 (P2X7R) is a novel molecular imaging target for neuroinflammation via PET. We have previously developed [11C]GSK1482160 as a promising P2X7R radioligand for imaging neuroinflammation. Here we report the synthesis and preliminary biological evaluation of a new P2X7R radioligand [18F]IUR-1601. Methods: The reference standard IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-fluoroethyl)-5-oxopyrrolidine-2-carboxamide) and its corresponding precursor (S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2-chloroethyl)-5-oxopyrrolidine-2-carboxamide were synthesized from tert-butyl (S)-5-oxopyrrolidine-2-carboxylate, fluoroethylbromide and chloroethylbromide, and 2-chloro-3-(trifluoromethyl)benzylamine. Another labeling precursor desmethyl-GSK1482160 was prepared from L-pyroglutamic acid and 2-chloro-3-(trifluoromethyl)benzylamine. One-step radiosynthesis of [18F]IUR-1601 from chloroethyl- precursor was first conducted and failed. Therefore, [18F]IUR-1601 was synthesized from desmethyl-GSK1482160 with [18F]FCH2CH2OTs, prepared from TsOCH2CH2OTs and K[18F]F/Kryptofix2.2.2, in two steps. The potency of IUR-1601 in comparison with GSK1482160 was determined by a ligand competitive binding assay using [11C]GSK1482160. Results : The overall chemical yields for IUR-1601 and its chloroethyl- precursor were 10-15% in 3 steps. The yield of desmethyl-GSK1482160 was 76% in 1 step. IUR-1601 and its chloroethyl- precursor are unstable under high temperature and strong base conditions, converting to (S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-5-oxo-1-vinylpyrrolidine-2-carboxamide by elimination reaction, which caused one-step synthesis of [18F]IUR-1601 to fail. In addition, [18F]fluoroethylation of amide requires high reaction temperature and strong base, thus both result in that radiochemical yield for two-step synthesis of [18F]IUR-1601 was very low, 1-3%. The radiochemical purity was >99%, and the specific activity was >2 Ci/µmol at EOB determined by a “spike” Methods: The binding affinity Ki for IUR-1601 and GSK1482160 is 4.3 and 5.1 nM, respectively. Conclusions : A new P2X7R radioligand [18F]IUR-1601 has been successfully radiosynthesized, and retains the P2X7R affinity of [11C]GSK1482160. The radiosynthesis optimization, automation and in vivo biological evaluation of [18F]IUR-1601 are currently underway. Research Support : Showalter Young Investigator Award and Indiana University Department of Radiology and Imaging Sciences.