Potent Cannabinergic Indole Analogues as Radioiodinatable Brain Imaging Agents for the CB1 Cannabinoid Receptor

• Published in: Journal of medicinal chemistry Vol. 48; no. 20; pp. 6386 - 6392
• Main Authors: Deng, Hongfeng, Gifford, Andrew N, Zvonok, Alexander M, Cui, Guangjian, Li, Xiuyan, Fan, Pusheng, Deschamps, Jeffrey R, Flippen-Anderson, Judith L, Gatley, S. John, Makriyannis, Alexandros
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 06.10.2005; Amer Chemical Soc
• Subjects: Animals; Autoradiography; Biological and medical sciences; Brain - metabolism; Chemistry, Medicinal; Crystallography, X-Ray; Hippocampus - metabolism; In Vitro Techniques; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacokinetics; Iodine Radioisotopes; Life Sciences & Biomedicine; Ligands; Medical sciences; Mice; Mice, Knockout; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacokinetics; Radioligand Assay; Radiopharmaceuticals - chemical synthesis; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Rats; Receptor, Cannabinoid, CB1 - genetics; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB2 - metabolism; Science & Technology; Spleen - metabolism; Stereoisomerism; Structure-Activity Relationship; AGONISTS; CB1 cannabinoid receptor; Agonist; Nitrogen heterocycle; Central nervous system; Encephalon; Racemic; Scintigraphic agent; Enantiomer; Piperidine derivatives; Bicyclic compound; Aromatic compound; Chemical synthesis; Radiolabelling; Rodentia; Iodine Isotopes; Ketone; In vitro; Biological activity; Autoradiography; Vertebrata; Mammalia; Mouse; Animal; Affinity; Benzenic compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050135l

A series of novel aminoalkylindoles was synthesized in an effort to develop compounds that are potent agonists at the CB1 cannabinoid receptor and that are also easily labeled with radioisotopes of iodine for biochemical and imaging studies. 2-Iodophenyl-[1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl]methanone (8, AM2233) had a very high affinity for the rat CB1 receptor, with most of the affinity residing with the (R)-enantiomer. Radioiodinated 8, (R)-8, and (S)-8 were prepared by radioiododestannylation of the tributyltin analogues in high yields, radiochemical purities, and specific radioactivities. In a mouse hippocampal membrane preparation with [131I](R)-8 as radioligand, racemic 8 exhibited a K i value of 0.2 nM compared with 1.6 nM for WIN55212-2. In autoradiographic experiments with mouse brain sections, the distribution of radioiodinated 8 was consistent with that of brain CB1 receptors. Again, very little specific binding was seen with the (S)-enantiomer [131I](S)-8 and none occurred with the (R)-enantiomer [131I](R)-8 in sections from CB1 receptor knockout mice. Radioiodinated 8 thus appears to be a suitable radioligand for studies of CB1 cannabinoid receptors.