Synthesis of carbon-11 labeled iodinated cocaine derivatives and their distribution in baboon brain measured using positron emission tomography.
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.
Yu
D W
DW
Department of Chemistry, Brookhaven National Laboratory, Upton, New York 11973.
Gatley
S J
SJ
Wolf
A P
AP
MacGregor
R R
RR
Dewey
S L
SL
Fowler
J S
JS
Schlyer
D J
DJ
D000818:Animals; D001667:Binding, Competitive; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002531:Cerebellum / Q000378:metabolism; D003042:Cocaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000378:metabolism; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism; D007455:Iodine; D007553:Isotope Labeling; D007700:Kinetics; D010215:Papio; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D001798:Blood Proteins; D002250:Carbon Radioisotopes; D007455:Iodine; D003042:Cocaine