Automated radiosyntheses of [6-O-methyl-11C]diprenorphine and [6-O-methyl-11C]buprenorphine from 3-O-trityl protected precursors

Abstract The antagonist [6- O -methyl- 11 C]diprenorphine and the mixed agonist/antagonist [6- O -methyl- 11 C]buprenorphine, radioligands for studying the opioid receptor system in vivo with positron emission tomography, were prepared by O -methylation of (3- O -trityl,6-desmethyl)diprenorphine and [3- O -trityl,6-desmethyl]buprenorphine, respectively, with [ 11 C]iodomethane. The use of the base-stable, acid labile trityl protecting group minimizes the formation of byproducts and allows reproducible radiosyntheses. The two-step syntheses were carried out in a fully automated system giving [6- O -methyl- 11 C]diprenorphine in a 13–19% radiochemical yield with a sp. act. of 15.5–23.8 GBq μmol −1 at EOS. The preparation takes 45 min from EOB. Similarly, [6- O -methyl- 11 C]buprenorphine is prepared in 50 min from EOB in 12.6–17% radiochemical yield, with a specific activity of 12.8–21.8 GBq μmol −1 at EOS. 13 C and 1 H NMR studies were used to characterize diprenorphine and buprenorphine derivatives and, in particular, to confirm the position of methylation.

[1]  V. Pike,et al.  The preparation of carbon-11 labelled diprenorphine: a new radioligand for the study of the opiate receptor system in vivo , 1985 .

[2]  Karl J. Friston,et al.  Endogenous opiate response to pain in rheumatoid arthritis and cortical and subcortical response to pain in normal volunteers using positron emission tomography. , 1991, International journal of clinical pharmacology research.

[3]  M. Barfield,et al.  Long-range proton spin-spin coupling , 1969 .

[4]  A. Wilson,et al.  Facile synthesis of [11C]buprenorphine for positron emission tomographic studies of opioid receptors. , 1990, International journal of radiation applications and instrumentation. Part A, Applied radiation and isotopes.

[5]  J. Ashburner,et al.  In vivo distribution of opioid receptors in man in relation to the cortical projections of the medial and lateral pain systems measured with positron emission tomography , 1991, Neuroscience Letters.

[6]  Jonathan M. Links,et al.  Comparison of [11C]Diprenorphine and [11C]Carfentanil Binding to Opiate Receptors in Humans by Positron Emission Tomography , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[7]  Alan A. Wilson,et al.  Mu‐opiate receptors measured by positron emission tomography are increased in temporal lobe epilepsy , 1988, Annals of neurology.

[8]  M. Welch,et al.  Sex-dependent differences in N-(3-[18F]fluoropropyl)-N-nordiprenorphine biodistribution and metabolism. , 1990, Journal of Nuclear Medicine.

[9]  A. Mallard,et al.  NMR Spectra and Stereochemistry of some 7‐Substituted 6,14‐Bridged Thebaine Derivatives , 1985 .

[10]  A. Goldstein,et al.  Site-directed alkylation of multiple opioid receptors. I. Binding selectivity. , 1984, Molecular pharmacology.

[11]  H. N. Wagner,et al.  Multicompartmental Analysis of [11C]-Carfentanil Binding to Opiate Receptors in Humans Measured by Positron Emission Tomography , 1989, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[12]  V J Cunningham,et al.  A method of studying pharmacokinetics in man at picomolar drug concentrations. , 1991, British journal of clinical pharmacology.

[13]  Dean F. Wong,et al.  Imaging Opiate Receptors in the Human Brain by Positron Tomography , 1985, Journal of computer assisted tomography.

[14]  Victor W. Pike,et al.  Regional cerebral opioid receptor studies with [11C]diprenorphine in normal volunteers , 1988, Journal of Neuroscience Methods.

[15]  B. Morris,et al.  A model of chronic pain in the rat: high-resolution neuroanatomical approach identifies alterations in multiple opioid systems in the periaqueductal grey , 1987, Brain Research.

[16]  Alan A. Wilson,et al.  Synthesis of carbon-11 labeled diprenorphine: A radioligand for positron emission tomographic studies of opiate receptors , 1987 .

[17]  Karl J. Friston,et al.  Cortical and subcortical localization of response to pain in man using positron emission tomography , 1991, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[18]  F. Wehrli 13C Spectral assignment and spin-lattice relaxation in medium-sized molecules , 1974 .

[19]  V. Pike,et al.  The radiosynthesis of nca [O‐methyl‐11C]viqualine, through an N‐trityl‐protected intermediate, as a potential pet radioligand for 5HT re‐uptake sites , 1990 .

[20]  W C Eckelman,et al.  S‐[18F]Acetylcyclofoxy: a useful probe for the visualization of opiate receptors in living animals , 1984, FEBS letters.

[21]  P. Portoghese,et al.  Pharmacological characterization in vivo of the novel opiate, beta-funaltrexamine. , 1982, The Journal of pharmacology and experimental therapeutics.

[22]  J. Lever,et al.  Two‐dimensional homonuclear and heteronuclear correlation NMR studies of diprenorphine: A prototypic 6α, 14α‐endo‐ethanotetrahydrothebaine , 1990 .

[23]  Karl J. Friston,et al.  Localization of responses to pain in human cerebral cortex. , 1992, Science.

[24]  C. Crouzel,et al.  Preparation of [11C]buprenorphine--a potential radioligand for the study of the opiate receptor system in vivo. , 1987, International journal of radiation applications and instrumentation. Part A, Applied radiation and isotopes.

[25]  Alan A. Wilson,et al.  Quantification of mu and non–mu opiate receptors in temporal lobe epilepsy using positron emission tomography , 1991, Annals of neurology.

[26]  J. Holaday,et al.  Multiple opioid receptors in endotoxic shock: evidence for delta involvement and mu-delta interactions in vivo. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[27]  W C Eckelman,et al.  Radiosynthesis of [18F]3-acetylcyclofoxy: a high affinity opiate antagonist. , 1985, The International journal of applied radiation and isotopes.

[28]  H N Wagner,et al.  Radiosynthesis of an opiate receptor binding radiotracer: [11C]carfentanil. , 1985, The International journal of applied radiation and isotopes.

[29]  E. J. Simon,et al.  Selective changes in μ, δ and ϰ opioid receptor binding in certain limbic regions of the brain in Alzheimer's disease patients , 1987, Brain Research.

[30]  John Ashburner,et al.  Dynamic monitoring of [11C]diprenorphine in rat brain using a prototype positron imaging device , 1991, Journal of Neuroscience Methods.

[31]  A. Takemori,et al.  Relative involvement of mu, kappa and delta receptor mechanisms in opiate-mediated antinociception in mice. , 1983, The Journal of pharmacology and experimental therapeutics.

[32]  P. Portoghese,et al.  Improved assays for the assessment of ϰ- and δ-properties of opioid ligands , 1982 .

[33]  Alan A. Wilson,et al.  Quantification of Human Opiate Receptor Concentration and Affinity Using High and Low Specific Activity [11C]Diprenorphine and Positron Emission Tomography , 1991, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[34]  B Sadzot,et al.  Imaging opiate receptors in the human brain with positron emission tomography. Potential applications for drug addiction research. , 1990, Acta psychiatrica Belgica.

[35]  A. Wolf,et al.  No-carrier-added (NCA) N-(3-[18F]fluoropropyl)-N-norbuprenorphine and N-(3-[18F]fluoropropyl)-N-nordiprenorphine--synthesis, anatomical distribution in mice and rats, and tomographic studies in a baboon. , 1990, International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology.