Synthesis and in vivo brain distribution of carbon-11-labeled delta-opioid receptor agonists

Three new radiolabeled compounds, [C-11]SNC80 ((+)-4-[(alpha R)-alpha-{(2S,5R)-4-allyl-2,5-dimethyl-l-piperazinyl}-3-[C-11]methoxyben zyl-N, N-diethylbenzamide), N,N-diethyl-4-[3-methoxyphenyl-l[C-11]methylpiperidin-4-ylidenemethyl)be nzamide and N,N-diethyl-4-[(1-[C-11] methylpiperidin-4-ylidene)phenylmethyl]benzamide, were prepared as potential in vivo radiotracers for the delta-opioid receptor. Each compound was synthesized by alkylation of the appropriate desmethyl compounds using [C-11]methyl triflate. In vivo biodistribution studies in mice showed very low initial brain uptake of all three compounds and no regional specific binding for [C-11]SNC80. A monkey positron emission tomography study of [C-11]SNC80 confirmed low brain permeability and uniform regional distribution of this class of opioid agonists in a higher species. Opioid receptor ligands of this structural class are thus unlikely to succeed as in vivo radiotracers, likely due to efficient exclusion from the brain by the P-glycoprotein efflux transporter.