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Design and synthesis of the CB1 selective cannabinoid antagonist AM281: A potential human SPECT ligand

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Abstract

In the search for a radioligand capable of imaging cannabinoid CB1 receptors in the living human brain by SPECT (single photon emission computed tomography), N-(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281) was synthesized. This compound is an analog of the potent, CB1 receptor selective antagonist SR141716A [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide]. AM281 bound to brain and spleen membrane preparations (CB1 and CB2 receptors, respectively) with K i values of 12 nM and 4200 nM, respectively. AM281 also inhibited the response of guinea-pig small intestine preparation to a cannabinoid receptor agonist. Thus, AM281 behaves as a CB1 receptor selective antagonist. Methods for the rapid, high-yield synthesis and purification of [123I]AM281 were developed, and transaxially reconstructed brain SPECT images obtained after continuous infusion of [123I]AM281 in baboons. Thus [123I]AM281 may be suitable for imaging CB1 receptors in humans.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences and Molecular and Cell Biology, U-92, University of Connecticut, 06269, Storrs, CT

    Ruoxi Lan, Qian Lu, Pusheng Fan & Alexandros Makriyannis

  2. Medical Department, Brookhaven National Laboratory, 11973, Upton, NY

    John Gatley & Nora D. Volkow

  3. Department of Biomedical Sciences, University of Aberdeen, AB9 1AS, Aberdeen, Scotland

    Susanthi R. Fernando & Roger Pertwee

  4. Institute of Material Sciences, University of Connecticut, 06269, Storrs, CT

    Alexandros Makriyannis

Authors
  1. Ruoxi Lan
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  2. Qian Lu
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  3. Pusheng Fan
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  4. John Gatley
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  5. Nora D. Volkow
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  6. Susanthi R. Fernando
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  7. Roger Pertwee
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  8. Alexandros Makriyannis
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Correspondence to Alexandros Makriyannis.

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Published June 20, 1999.

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Lan, R., Lu, Q., Fan, P. et al. Design and synthesis of the CB1 selective cannabinoid antagonist AM281: A potential human SPECT ligand. AAPS PharmSci 1, 4 (1999). https://doi.org/10.1208/ps010204

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  • DOI: https://doi.org/10.1208/ps010204

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