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
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 1345 West 16th Street, Room 202, Indianapolis, IN 46202, USA.
Department of Radiology and Imaging Sciences, Indiana University School of Medicine, 1345 West 16th Street, Room 202, Indianapolis, IN 46202, USA.
Appl Radiat Isot. 2019 Feb;144:10-18. doi: 10.1016/j.apradiso.2018.11.006. Epub 2018 Nov 16.
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.
P2X7R的过表达与神经炎症相关，并在各种神经退行性疾病中起重要作用。GSK1482160的[F]氟丙基衍生物[F]IUR-1602已首次制备并作为一种新的潜在P2X7R放射性配体进行研究。参考标准品IUR-1602由(S)-5-氧代吡咯烷-2-羧酸叔丁酯、氟丙基溴和2-氯-3-(三氟甲基)苄胺经三步合成，总化学产率为13%。目标示踪剂[F]IUR-1602由去甲基-GSK1482160与3-[F]氟丙基对甲苯磺酸酯经两步合成，3-[F]氟丙基对甲苯磺酸酯由1,3-丙二醇双(4-甲基苯磺酸酯)和K[F]F/Kryptofix2.2.2制备，通过HPLC结合SPE分离，衰变校正后的放射化学产率为2-7%。放射化学纯度>99%，轰击结束时（EOB）的摩尔活度为74-370 GBq/μmol。使用[C]GSK1482160通过放射性配体竞争结合试验确定IUR-1602与GSK1482160相比的效力，IUR-1602和GSK1482160的结合亲和力K值分别为23.6和3.07 nM。最初的体外评估结果表明，[F]IUR-1602的效力比[C]GSK1482160低8倍，这使得无法在动物和人体中对[F]IUR-1602进行进一步的体内评估。
