Background

[PubMed]

There are two subtypes of cannabinoid receptors in mammalian tissues: CB1 and CB2 (1, 2). CB1 receptors are expressed abundantly in neuronal terminals in the central nervous system (CNS) and some peripheral tissues to inhibit neurotransmitter release. CB1 receptors are found predominantly in the striatum, hippocampus, substantia nigra, globus pallidus, and cerebellum. The CB2 receptors are present mainly on immune cells to modulate cytokine release. Both receptor subtypes are coupled through G_i/o proteins to inhibit adenylate cyclase and to modulate potassium and calcium channels. CB1 receptors have been demonstrated to be involved in analgesia, regulation of food intake, and control of movement in normal subjects (3). Alteration of CB1 receptor function has been implicated in a number of human diseases such as depression, schizophrenia, and obesity (4-6).

Δ9-Tetrahydrocannabinol (THC) is a major active cannabinoid that is found in marijuana and activates CB1 receptors (7). THC has a very high lipophilicity (log D_7.4 value of 7), which causes imaging studies using radiolabeled THC to be unsuccessful because of slow entry into the brain and high nonspecific binding in the brain. However, a high lipophilicity is essential for binding to CB1 receptors, and an optimal lipophilicity (log D_7.4 1–4) is required for crossing the blood–brain barrier (BBB). Existing radiolabeled ligands are mainly analogs of the antagonist rimonabant (SR141716A) and the agonist WIN 55,212-2, which also exhibit high nonspecific binding and lipophilicity, limiting their application in imaging (8). Therefore, there is a need to lower the lipophilicity of the CB1 radioligands with little effect on binding affinity and ability to cross the BBB. 1-(2,4-Dichlorophenyl)-5-(4-[¹²³I]iodophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid N',N'-dimethyl-hydrazide ([¹²³I]Me₂Pyr) is a CB1 analog of N-(morpholin-4-yl)-5-(4-[¹²³I]iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide ([¹²³I]AM281) with the N-heterocyclic residue substituted by a dimethylamino group (9). [¹²³I]Me₂Pyr is being developed as a single-photon emission computed tomography (SPECT) agent for the non-invasive study of CB1 receptors in the brain.

Synthesis

[PubMed]

Gielow et al. (9) reported synthesis of [¹²³I]Me₂Pyr by radioiododestannylation reaction of the tributyltin precursor with [¹²³I]iodide in the presence of HCl and chloramine-T. Radiochemical yields were 48% after high-performance liquid chromatography purification. Specific activities were >75 GBq/μmol (>2 Ci/μmol) with a radiochemical purity of >92%.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Gielow et al. (9) reported that the lipophilicity values were 3.7 for AM281, 4.5 for Me₂Pyr, and 4.8 for SR141716A.

Animal Studies

Human Studies

[PubMed]

References

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2.

Pertwee R.G. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther. 1997;74(2):129–80. [PubMed: 9336020]

3.

Pertwee, R.G., Pharmacological actions of cannabinoids. Handb Exp Pharmacol, 2005(168): p. 1-51. [PubMed: 16596770]

4.

Gambi F., De Berardis D., Sepede G., Quartesan R., Calcagni E., Salerno R.M., Conti C.M., Ferro F.M. Cannabinoid receptors and their relationships with neuropsychiatric disorders. Int J Immunopathol Pharmacol. 2005;18(1):15–9. [PubMed: 15698507]

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De Vries T.J., Schoffelmeer A.N. Cannabinoid CB1 receptors control conditioned drug seeking. Trends Pharmacol Sci. 2005;26(8):420–6. [PubMed: 15992935]

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Guzman M., Sanchez C. Effects of cannabinoids on energy metabolism. Life Sci. 1999;65(6-7):657–64. [PubMed: 10462066]

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Martin B.R. Cellular effects of cannabinoids. Pharmacol Rev. 1986;38(1):45–74. [PubMed: 2872689]

8.

Gifford A.N., Makriyannis A., Volkow N.D., Gatley S.J. In vivo imaging of the brain cannabinoid receptor. Chem Phys Lipids. 2002;121(1-2):65–72. [PubMed: 12505691]

9.

Gielow P., Klinge P., Knapp W.H., Berding G. Synthesis and preliminary biological evaluation of [123I]Me2Pyr, a new potential ligand for imaging of central cannabinoid CB1 receptors. Appl Radiat Isot. 2006;64(7):763–8. [PubMed: 16554168]