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Pharmacokinetics of [11C]-labeled aminoalkylindole derivatives for PET imaging of cannabinoid CB1 receptors in baboons

¹ Medical, Brookhaven National Laboratory, Brookhaven, New York; ² Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts

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Objectives: Cannabinoid receptors have been implicated in many central and peripheral disorders and a number of promising PET radioligands have been reported (Willis et al., 2005; Horti et al., 2006; Yasuno et al., 2007). The purpose of this study was to synthesize and evaluate a series of structurally similar [11C]aminoalkylindole derivatives as potential CB1 receptor radioligands. [11C]labeled (7-methoxy-1-((1-methylpiperidin-2-yl)methyl)-1H-indole-3-yl)(naphthalene-1-yl)methanone 1; (1-((1-methylpiperidin-2-yl)methyl)-1H-indole-3-yl)(naphthalene-1-yl)methanone 2 and (1-((4-methylmorphli-3-yl)methyl)-1H-indole-3-yl)(naphthalene-1-yl)methanone 3 were studied.

Methods: Radioligands 1, 2 and 3 were prepared by N-alkylation of the corresponding desmethyl precursors with 11CH3I. LogD, % unbound to plasma proteins, pharmacokinetics in brain and arterial plasma and distribution volumes were compared. Coinjection studies with rimonabant (0.5mg/kg) were also done.

Results: LogD values were 3.77, 3.56, 3.38 and plasma free fractions were 2.04, 0.36 and 0.31 for 1, 2 and 3 respectively. Each radiotracer showed relatively uniform distribution in the brain with rapid uptake and clearance between 20-60 min with 2 showing the slowest clearance. Peak uptake in the brain was 0.009% ID/cc for 1 and 0.016% ID/cc for 2 and 3. Plasma metabolism and clearance was rapid for each radiotracer. Rimonabant did not inhibit radioactivity uptake in the brain.

Conclusions: Rimonabant, an antagonist, did not inhibit radioactivity uptake but we plan to use a suitable agonist for further investigations. Radiotracer 2 is the most promising of this series and will be further evaluated in PET imaging studies of CB1 receptors.

Research Support: DOE-OBER and NIH (K05-DA020001).

This Article Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Reid, A. Articles by Fowler, J. PubMed Articles by Reid, A. Articles by Fowler, J.