新的高强度高选择性阿片μ受体激动剂[11C]-羟甲芬太尼的合成

羟甲芬太尼(I)是一个新的高强度高选择性阿片μ受体激动剂。本文用cis-A-N-[1-(2-羟基-2-苯乙基)-3-甲基-4-哌啶基]-苯胺(II)或cis-N-[1-(苯甲酰甲基)-3-甲基-4-哌啶基]-苯胺(III)作为前体合成了[¹¹C]-羟甲芬太尼,以便用正电子发射断层扫描(PET)来观察μ受体。通过水解cis-A-羟甲芬太尼(I)和cis-N-[1-(苯甲酰甲基)-3-甲基-4-哌啶]-N-苯基丙酰胺(cis-IV)的4-N-丙酰基分别获得II和III。溴乙烷的格氏试剂与回旋加速器产生的[¹¹C]-二氧化碳反应后继而直接加入邻苯二甲酸二酰氯和2,6-二叔丁基吡啶生成同位素标记中间体[¹¹C]-丙酰氯。[¹¹C]-丙酰氯与OH-前体(II)反应后再经HPLC分离纯化直接得[¹¹C]-羟甲芬太尼;[¹¹C]-丙酰氯与酮-前体(III)反应后,再用硼氢化钠甲醇溶液处理,然后进行HPLC分离纯化得[¹¹C]-羟甲芬太尼。两种方法均可获得ll.1～14.8GBq/μmol的特异性放射化学纯[¹¹C]-羟甲芬太尼。总共耗时为40～50min(EOB)。

SYNTHESIS OF [11C] -OHMEFENTANYL,A NEW,HIGHLY POTENT AND SELECTIVE AGONIST FOR OPIATE μ-RECEPTOR

Ohmefentanyl I is a new,highly potent and selective agonist for opiate μ-recptor. In order to visualize the μ-receptor by Positron Emission Tomography(PET),I labelcd with carbon-11 was synthesized using OH-precursor II or keto-precursor III.The OH-precursor Il was obtained by hydrolysis of cis-A-ohmefentanyl in 6 mol/L hydrochloric acid and the keto-precursor III was prepared by hydrolysis of cis-IV in 8 mol/L hydrochloric acid.The active intermediate[¹¹C]-propionyl chloride was prepared by the reaction between Grignard reagent ethylmagnesium bromide and cyclotron-produced[¹¹C]-carbon dioxide,followed by direct treatment of the radio-complex with phthaloyldichloride and 2,6-di-t-butylpyridine. Reaction of the OH-precursor Il with[¹¹C]-propionyl chlorideorreaction of the keto-precursor IIl with[¹¹C]-propionyl chloride and treatment with sodiumborohydride followed by HPLC separation all afforded[¹¹C]-ohmefentanyl with high specific activityof ll.1～14.8 GBq/μmol(300～400 mCi/μmo1)at 45～50 minutes after the end of bombardment(EOB).