A method for parallel solid-phase synthesis of iodinated analogs of the cannabinoid receptor type I (CB₁) inverse agonist rimonabant.
Rimonabant (acomplia) is a 1,5-diarylpyrazole derivative that acts as a type 1 cannabinoid receptor (CB₁) inverse agonist. Here, we overview the role of this type of molecule in regulation of these receptors and their potential as starting points for the development of molecular probes to image the central nervous system (CNS). We then describe a novel protocol for the solid-phase parallel chemical synthesis of iodinated rimonabant analogs using germanium-functionalized, cross-linked polystyrene as the solid-support (or "resin"). The method allows for rapid derivatization at the key C-3 position of rimonabant from a common resin-bound precursor. The desired iodinated analogs are then obtained by ipso-iododegermylative cleavage from the resin using sodium iodide/N-chlorosuccinimide (NCS) in a fashion that ought to be readily adapted to the rapid preparation of isotopically labeled iodine derivatives for molecular imaging of CNS activity by positron emission tomography (PET, using ¹²⁴I) and single photon emission computerized tomography (SPECT, using (¹²³I) techniques. Toward this goal, we also show that the NCS-derived succinimide by-product that is released from the resin concomitantly with the potential imaging probe molecules can be readily and selectively removed by treatment of the crude soluble product mixture with a solid-supported hydrazide scavenger resin.
Department of Chemistry, Imperial College, London, United Kingdom.
Alan C
AC
Spivey
Chih-Chung
CC
Tseng
D000818:Animals; D001921:Brain / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D054314:Drug Inverse Agonism; D054879:Halogenation; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry; D011869:Radioligand Assay / Q000379:methods; D043884:Receptor, Cannabinoid, CB1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077285:Rimonabant
D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant