SYNTHESIS AND BIODISTRIBUTION OF THE ALPHA-2-ADRENERGIC RECEPTOR ANTAGONIST (C-11)WY26703 - USE AS A RADIOLIGAND FOR POSITRON EMISSION TOMOGRAPHY

The purpose of these experiments was to label an alpha2-adrenergic receptor ligand with a positron emitting isotope and then test this radioligand in vivo. No-carrier-added [C-11]WY26703 was synthesized by methylation of its desmethyl precursor, WY27050 with [C-11]H3I followed by purification with HPLC in 14% yield in a synthesis time of 35 min from EOB. K(i) values for unlabeled WY26703, ranged from 0.52-1.55 nM in tissues that express a single alpha2-adrenergic receptor subtype. Tail vein injections of [C-11]WY26703 in mice revealed that the compound was distributed in the brain, heart, lungs, spleen, and kidneys. In the brains of rats treated with atipamezole, an alpha2-adrenergic receptor antagonist, there was no decrease in [C-11] accumulation indicating a lack of observable specific binding of the radioligand. When brain tissue was homogenized and filtered, however, atipamezole decreased [C-11] activity by 53%. Therefore, [C-11]WY26703 crosses the blood-brain barrier and specifically binds to alpha2-adrenergic receptors with high affinity. Atipamezole treatment decreased only the area of the locus coeruleus [C-11] value of the various regions of the brain. The affinity, however, of [C-11]WY26703 does not appear to distinguish alpha2-receptors from nonspecific binding sites. PET study of [C-11]WY26703 in a Rhesus monkey showed that influx of [C-11]WY26703 into the brain was high for the first few minutes but radioactivity then declined rapidly and did not retain in a specific brain region. This suggests that [C-11]WY26703 may not be a useful ligand for imaging human alpha2-adrenergic receptors by positron emission tomography.