Synthesis of carbon-11 labeled iodinated cocaine derivatives and their distribution in baboon brain measured using positron emission tomography

Article abstract of 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 α₁-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 ? cocaine > m-iodo ? o-iodo.