Synthesis and biodistribution of the alpha 2-adrenergic receptor antagonist (11C)WY26703. Use as a radioligand for positron emission tomography.
The purpose of these experiments was to label an alpha 2-adrenergic receptor ligand with a positron emitting isotope and then test this radioligand in vivo. No-carrier-added [11C]WY26703 was synthesized by methylation of its desmethyl precursor, WY27050 with [11C]H3I followed by purification with HPLC in 14% yield in a synthesis time of 35 min from EOB. Ki values for unlabeled WY26703, ranged from 0.52-1.55 nM in tissues that express a single alpha 2-adrenergic receptor subtype. Tail vein injections of [11C]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 alpha 2-adrenergic receptor antagonist, there was no decrease in [11C] accumulation indicating a lack of observable specific binding of the radioligand. When brain tissue was homogenized and filtered, however, atipamezole decreased [11C] activity by 53%. Therefore, [11C]WY26703 crosses the blood-brain barrier and specifically binds to alpha 2-adrenergic receptors with high affinity. Atipamezole treatment decreased only the area of the locus coeruleus [11C] value of the various regions of the brain. The affinity, however, of [11C]WY26703 does not appear to distinguish alpha 2-receptors from nonspecific binding sites. PET study of [11C]WY26703 in a Rhesus monkey showed that influx of [11C]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 [11C]WY26703 may not be a useful ligand for imaging human alpha 2-adrenergic receptors by positron emission tomography.
Department of Pharmacology, University of Nebraska Medical Center, Omaha.
R C
RC
Pleus
C Y
CY
Shiue
G G
GG
Shiue
J A
JA
Rysavy
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H
Huang
K G
KG
Cornish
J J
JJ
Sunderland
D B
DB
Bylund
D000319:Adrenergic beta-Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes; D002460:Cell Line; D005260:Female; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D011807:Quinolizines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000502:physiology; D014055:Tomography, Emission-Computed
D000319:Adrenergic beta-Antagonists; D002250:Carbon Radioisotopes; D011807:Quinolizines; C038538:Wy 26703