Synthesis and in vitro biological evaluation of new P2X7R radioligands [11C] halo-GSK1482160 analogs

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:29

Article

Gao, Mingzhang¹  Wang, Min¹  Meyer, Jill A.¹  Territo, Paul R.¹  Hutchins, Gary D.¹  Zarrinmayeh, Hamideh¹  Zheng, Qi-Huang¹ 

[1] Indiana Univ Sch Med, Dept Radiol & Imaging Sci, 1345 West 16th St,Room 202, Indianapolis, IN 46202 USA

关键词: [C-11]Fialo-GSK1482160 (F-,Br-, and I-);    Purinergic P2X7 receptor (P2X7R);    Radiosynthesis;    Competitive binding assay;    Positron emission tomography (PET);   

DOI  :  10.1016/j.bmcl.2019.04.018

来源: Elsevier

【 摘 要 】

The reference standards halo-GSK1482160 (F-, Br-, and I-) and their corresponding precursors desmethyl-halo-GSK1482160 (F-, Br-, and I-) were synthesized from (S)-1-methyl-5-oxopyrrolidine-2-carboxylic acid or (S)-5-oxopyrrolidine-2-carboxylic acid and 2-halo-3-(trifluoromethyl)benzylamine (F-, Br-, and I-) in one step with 45-93% yields. The target tracers [C-11]halo-GSK1482160 (F-, Br-, and I-) were prepared from desmethyl-halo-GSK1482160 (F-, Br-, and I-) with [C-11]CH3OTf under basic conditions (NaOH-Na2CO3, solid, w/w 1:2) through N-[C-11]methylation and isolated by HPLC combined with SPE in 40-50% decay corrected radiochemical yield. The radiochemical purity was > 99%, and the molar activity (A(M)) at end of bombardment (EOB) was 370-740 GBq/mu mol. The potency of halo-GSK1482160 (F-, Br-, and I-) in comparison with GSK1482160 (Cl-) was determined by a radioligand competitive binding assay using [C-11]GSK1482160, and the binding affinity K-i values for halo-GSK1482160 (F-, Br-, and I-) and GSK1482160 (Cl-) are 54.2, 2.5, 1.9 and 3.1 nM, respectively.

【 授权许可】

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