Yu D W, Gatley S J, Wolf A P, MacGregor R R, Dewey S L, Fowler J S, Schlyer D J
Department of Chemistry, Brookhaven National Laboratory, Upton, New York 11973.
J Med Chem. 1992 Jun 12;35(12):2178-83. doi: 10.1021/jm00090a005.
Three iodine-substituted derivatives of cocaine, methyl esters of 3-[(2'-, 3'-, and 4'-iodobenzoyl)oxy]-8-methyl-[1R-(exo,exo)]-8- azabicyclo[3.2.1]octane-2 carboxylic acid (2a-c), were synthesized and subjected to N-demethylation to give the corresponding noriodococaines 3-[(2'-,3'-, and 4'-iodobenzoyl)oxy]-[1R-(exo,exo)]-8- azabicyclo[3.2.1]-octane-2-carboxylic acid (3a-c). These were remethylated with [11C]CH3I to give the [N-11C-methyl]iodococaines 4a-c which were examined in baboon brain in vivo using positron emission tomography (PET). Compared to [N-11C]cocaine itself the regional distributions were changed from a highly specific localization in the corpus striatum to more diffuse patterns which included the cerebellum and cortex. Peak brain uptakes and clearance kinetics were also changed. [N-11C]-o-Iodococaine (4a) had a peak uptake in the striatum at 4-5 min after injection of only 17% that of cocaine in the same animal. The peak uptake of [N-11C]-p-iodococaine (4c) was 60% of that of [N-11C]cocaine and a clearance half-time of approximately 55 min, twice that of [N-11C]cocaine. [N-11C]-m-Iodococaine (4b) displayed half the uptake of [N-11C]cocaine, buts its clearance was similar to that of the parent molecule. The fractions of unmetabolized tracer in blood plasma at 1-30 min were higher for 4a-c than for [N-11C]cocaine. Plasma protein binding experiments showed 10%, 0.3%, 1.6%, and 6% as the free fraction for cocaine and o-, m-, and p-iodococaines respectively, consistent with the low brain uptake observed for the ortho isomer, and implicated alpha 1-acid glycoprotein as responsible for the low free fraction of o-iodococaine. The potencies of 2a-c to displace tritiated cocaine from striatal membranes were p-iodo approximately cocaine greater than m-iodo approximately o-iodo.
合成了可卡因的三种碘取代衍生物，即3-[(2'-、3'-和4'-碘苯甲酰基)氧基]-8-甲基-[1R-(外向，外向)]-8-氮杂双环[3.2.1]辛烷-2-羧酸的甲酯(2a - c)，并对其进行N-去甲基化反应，得到相应的去甲碘可卡因，即3-[(2'-、3'-和4'-碘苯甲酰基)氧基]-[1R-(外向，外向)]-8-氮杂双环[3.2.1]辛烷-2-羧酸(3a - c)。用[11C]CH3I对这些化合物进行再甲基化反应，得到[N-11C-甲基]碘可卡因4a - c，并用正电子发射断层扫描(PET)在狒狒脑中进行了体内研究。与[N-11C]可卡因本身相比，其区域分布从纹状体中的高度特异性定位变为更弥散的模式，包括小脑和皮质。脑内摄取峰值和清除动力学也发生了变化。[N-11C]-邻碘可卡因(4a)在注射后4 - 5分钟时在纹状体中的摄取峰值仅为同一动物中可卡因摄取峰值的17%。[N-11C]-对碘可卡因(4c)的摄取峰值为[N-11C]可卡因摄取峰值的60%，清除半衰期约为55分钟，是[N-11C]可卡因的两倍。[N-11C]-间碘可卡因(4b)的摄取量为[N-11C]可卡因摄取量的一半，但其清除情况与母体分子相似。在1 - 30分钟时，血浆中未代谢示踪剂的比例对于4a - c高于[N-11C]可卡因。血浆蛋白结合实验表明，可卡因、邻碘可卡因、间碘可卡因和对碘可卡因的游离比例分别为10%、0.3%、1.6%和6%，这与邻位异构体观察到的低脑摄取情况一致，并表明α1-酸性糖蛋白是邻碘可卡因低游离比例的原因。2a - c从纹状体膜上取代氚标记可卡因的效力为对碘可卡因＞间碘可卡因＞邻碘可卡因。
