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

Pichika, Rama; Jewett, Douglas M.; Sherman, Philip S.; Traynor, John R.; Husbands, Stephen M.; Woods, James H.; Kilbourn, Michael R.

doi:10.1016/j.nucmedbio.2010.06.002

« Previous Next »Nuclear Medicine and Biology
Volume 37, Issue 8 , Pages 989-996, November 2010

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

Rama Pichika
- Department of Radiology, University of California, San Diego, CA, USA
- Corresponding author. Tel.: +1 858 373 2860; fax: +1 858 373 2865.
Douglas M. Jewett
- Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Philip S. Sherman
- Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
John R. Traynor
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Stephen M. Husbands
- Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom
James H. Woods
- Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Michael R. Kilbourn
- Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA

Received 21 April 2010; received in revised form 20 May 2010; accepted 1 June 2010. published online 26 July 2010.

Abstract

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 positron emission tomography 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.