Synthesis and In Vivo Brain Distribution of Carbon-11 Labeled δ-Opioid Receptor Agonists

摘要

Three new radiolabeled compounds, [¹¹C]SNC80 ((+)-4-[(αR)- α-{(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl}-3-[¹¹C]methoxybenzyl-N,N-diethylbenzamide), N,N-diethyl-4-[3-methoxyphenyl-1-[¹¹C]methylpiperidin-4-ylidenemethyl)benzamide, and N,N-diethyl-4-[(1-[¹¹C]methylpiperidin-4-ylidene)phenylmethyl]benzamide, were prepared as potential in vivo radiotracers for the δ opioid receptor. Each compound was synthesized by alkylation of the appropriate desmethyl compounds using [¹¹C]methyl triflate. In vivo biodistribution studies in mice showed very low initial brain uptake of all three compounds, and no regional specific binding for [¹¹C]SNC80. A monkey PET study of [¹¹C]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.