Mapping cocaine binding sites in human and baboon brain in vivo

Abstract

The first direct measurements of cocaine binding in the brain of normal human volunteers and baboons have been made by using positron emission tomography (PET) and tracer doses of [N-11C-methyl]-(-)-cocaine ([11C]cocaine). Cocaine's binding and release from brain are rapid with the highest regional uptake of carbon-11 occurring in the corpus striatum at 4-10 minutes after intravenous injection of labeled cocaine. This was followed by a clearance to half the peak value at about 25 minutes with the overall time course paralleling the previously documented time course of the euphoria experienced after intravenous cocaine administration. Blockade of the dopamine reuptake sites with nomifensine reduced the striatal but not the cerebellar uptake of [11C]cocaine in baboons indicating that cocaine binding is associated with the dopamine reuptake site in the corpus striatum. A comparison of labeled metabolites of cocaine in human and baboon plasma showed that while cocaine is rapidly metabolized in both species, the profile of labeled metabolites is different, with baboon plasma containing significant amounts of labeled carbon dioxide, and human plasma containing no significant labeled carbon dioxide. These studies demonstrate the feasibility of using [11C]cocaine and PET to map binding sites for cocaine in human brain, to monitor its kinetics, and to characterize its binding mechanism by using appropriate pharmacological challenges.

Serotonin Transporters in Dopamine Transporter Imaging: A Head-to-Head Comparison of Dopamine Transporter SPECT Radioligands 123I-FP-CIT and 123I-PE2I

“…Cocai ne labeled with 11 C was the first radioligand to be used for imaging the cerebral dopamine transporter (DAT) in vivo (1), but several other radioligands have subsequently been developed and tested as PET or SPECT ligands. With the introduction of 2-b-carbomethoxy-3b-(4-iodophenyl)-tropane ( 123 I-b-CIT) in 1991 (2), brain imaging of the DAT became a clinically useful method for supplementary diagnosis of movement disorders.…”

Positron Emission Tomography Studies of Potential Mechanisms Underlying Phencyclidine-Induced Alterations in Striatal Dopamine

“…In all studies, dynamic PET scanning commenced simultaneously with 11 C-raclopride injection and was performed for 60 min in a Siemens HR+using the following scanning protocol: 10 scans with a 1-min interval followed by 10 scans with a 5-min interval. For 11 C-cocaine (synthesized according to Fowler et al, 1989), the scanning protocol was four scans with a 0.5-min interval followed by four scans with a 1.0-min interval, four scans with a 2.0-min interval, four scans with a 5.0-min interval, and four scans with a 7.0-min interval. …”

Pet Imaging Studies in Drug Abuse Research

“…making ["C]methyl iodide first by the wet chemical methods (Langstrom et al, 1976) and recently by the gas phase method Link et al, 1995) revolutionized tracer development and allowed the synthesis of many labeled compounds for measuring drug pharmacokinetics such as [%]cocaine (Fowler et al, 1989) and ["Clmethylphenidate (Ding et al., 1994) as well as ["Clraclopride, (Farde et al, 1986) the key radiotracer for measuring dopamine D2 receptor availability and drug-induced changes in dopamine concentration .…”

“…Brain Pharmacokinetics: At tracer doses, [N-"C-methyl]cocaine has a very high and rapid uptake and clearance in the human striatum and clearance half-time of about 20 minutes (Fowler et al, 1989). Inhibition of norepinephrine transporter with desipramine did not change (Telang et al, 1999).…”

“…Rapid reproducible methods for 2 I I. '*.making ["C]methyl iodide first by the wet chemical methods (Langstrom et al, 1976) and recently by the gas phase method Link et al, 1995) revolutionized tracer development and allowed the synthesis of many labeled compounds for measuring drug pharmacokinetics such as [%]cocaine (Fowler et al, 1989) and ["Clmethylphenidate (Ding et al., 1994) as well as ["Clraclopride, (Farde et al, 1986) the key radiotracer for measuring dopamine D2 receptor availability and drug-induced changes in dopamine concentration .Tracer Kinetics: It is widely appreciated that the application of tracer kinetics in the context of specific interventions (pharmacological, isotope, stereochemistry) is a key issue in being able to sensitively measure the availability of a specific molecular target (Mintun et al, 1984). The advantages and limitations of obtaining absolute concentrations of molecular targets and the confounding influence of changes in blood flow on kinetic terms which can be derived from a radiotracer study have generated much research and controversy.…”