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Synthesis of carbon-11 labeled iodinated cocaine derivatives and their distribution in baboon brain measured using positron emission tomography. 1992

D W Yu, and S J Gatley, and A P Wolf, and R R MacGregor, and S L Dewey, and J S Fowler, and D J Schlyer
Department of Chemistry, Brookhaven National Laboratory, Upton, New York 11973.

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.

UI MeSH Term Description Entries
D007455 Iodine A nonmetallic element of the halogen group that is represented by the atomic symbol I, atomic number 53, and atomic weight of 126.90. It is a nutritionally essential element, especially important in thyroid hormone synthesis. In solution, it has anti-infective properties and is used topically. Iodine-127,Iodine 127
D007553 Isotope Labeling Techniques for labeling a substance with a stable or radioactive isotope. It is not used for articles involving labeled substances unless the methods of labeling are substantively discussed. Tracers that may be labeled include chemical substances, cells, or microorganisms. Isotope Labeling, Stable,Isotope-Coded Affinity Tagging,Isotopically-Coded Affinity Tagging,Affinity Tagging, Isotope-Coded,Affinity Tagging, Isotopically-Coded,Isotope Coded Affinity Tagging,Labeling, Isotope,Labeling, Stable Isotope,Stable Isotope Labeling,Tagging, Isotope-Coded Affinity,Tagging, Isotopically-Coded Affinity
D007700 Kinetics The rate dynamics in chemical or physical systems.
D010215 Papio A genus of the subfamily CERCOPITHECINAE, family CERCOPITHECIDAE, consisting of five named species: PAPIO URSINUS (chacma baboon), PAPIO CYNOCEPHALUS (yellow baboon), PAPIO PAPIO (western baboon), PAPIO ANUBIS (or olive baboon), and PAPIO HAMADRYAS (hamadryas baboon). Members of the Papio genus inhabit open woodland, savannahs, grassland, and rocky hill country. Some authors consider MANDRILLUS a subgenus of Papio. Baboons,Baboons, Savanna,Savanna Baboons,Baboon,Baboon, Savanna,Papios,Savanna Baboon
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D001798 Blood Proteins Proteins that are present in blood serum, including SERUM ALBUMIN; BLOOD COAGULATION FACTORS; and many other types of proteins. Blood Protein,Plasma Protein,Plasma Proteins,Serum Protein,Serum Proteins,Protein, Blood,Protein, Plasma,Protein, Serum,Proteins, Blood,Proteins, Plasma,Proteins, Serum
D001921 Brain The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM. Encephalon
D002250 Carbon Radioisotopes Unstable isotopes of carbon that decay or disintegrate emitting radiation. C atoms with atomic weights 10, 11, and 14-16 are radioactive carbon isotopes. Radioisotopes, Carbon
D002531 Cerebellum The part of brain that lies behind the BRAIN STEM in the posterior base of skull (CRANIAL FOSSA, POSTERIOR). It is also known as the "little brain" with convolutions similar to those of CEREBRAL CORTEX, inner white matter, and deep cerebellar nuclei. Its function is to coordinate voluntary movements, maintain balance, and learn motor skills. Cerebella,Corpus Cerebelli,Parencephalon,Cerebellums,Parencephalons
D003042 Cocaine An alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake. Cocaine HCl,Cocaine Hydrochloride,HCl, Cocaine,Hydrochloride, Cocaine

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