Synthesis and in vivo brain distribution of carbon-11-labeled δ-opioid receptor agonists.
Three new radiolabeled compounds, [(11)C]SNC80 ((+)-4-[(αR)-α-{(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl}-3-[(11)C]methoxybenzyl-N,N-diethylbenzamide), N,N-diethyl-4-[3-methoxyphenyl-1-[(11)C]methylpiperidin-4-ylidenemethyl)benzamide and N,N-diethyl-4-[(1-[(11)C]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 [(11)C]methyl triflate. In vivo biodistribution studies in mice showed very low initial brain uptake of all three compounds and no regional specific binding for [(11)C]SNC80. A monkey positron emission tomography study of [(11)C]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.
Department of Radiology, University of California, San Diego, CA, USA. rpichika@ucsd.edu
Rama
R
Pichika
Douglas M
DM
Jewett
Philip S
PS
Sherman
John R
JR
Traynor
Stephen M
SM
Husbands
James H
JH
Woods
Michael R
MR
Kilbourn
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D000882:Haplorhini; D008024:Ligands; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000378:metabolism* / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011854:Radiochemistry; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000378:metabolism
D001549:Benzamides; D002250:Carbon Radioisotopes; D008024:Ligands; D010879:Piperazines; D017465:Receptors, Opioid, delta; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide