title: Pharmacological characterisation of novel alpha 2-adrenoceptor antagonists as potential brain imaging agents.
abstract: Development of suitable imaging ligands to facilitate in vivo characterisation of alpha(2)-adrenoceptors has been limited in its success. In the present study, a series of iodinated derivatives and a fluorinated derivative of the classical alpha(2)-adrenoceptor antagonist, idazoxan, have been evaluated as potential imaging ligands. These compounds are based on the structure of idazoxan but more closely resemble the selective alpha(2)-adrenoceptor antagonists 2-methoxy-idazoxan (RX821002) and 2-ethoxy-idazoxan (RX811059). Preliminary studies, investigating their affinities at alpha(2)-adrenoceptors, using brain membranes prepared from a variety of species, and their ability to antagonise UK14, 304-induced inhibition of twitch in mouse vas deferens highlighted 2-iodopropoxy-idazoxan and 2-fluoroethoxy-idazoxan as the most promising candidates. Further characterisation of these two compounds showed they had a good selectivity for alpha(2)-adrenoceptors compared with imidazoline(2)-binding sites and beta-adrenoceptors. Additional functional studies also showed a lack of intrinsic activity at alpha(2)-adrenoceptors. Following intravenous injection, both compounds were able to cross the blood brain barrier when tested using an ex vivo binding assay. These data show that both 2-iodopropoxy-idazoxan and 2-fluoroethoxy-idazoxan have binding and functional properties suitable for imaging ligands. Further studies using radiolabelled forms of these ligands and a more extensive characterisation of their binding profiles are necessary but these initial evaluations demonstrate their potential.
authors.affiliation: Psychopharmacology Unit, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK.
authors.forename: Emma S J
authors.initials: ES
authors.lastname: Robinson
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Tyacke
authors.forename: Louise
authors.initials: L
authors.lastname: Finch
authors.forename: Graham
authors.initials: G
authors.lastname: Willmott
authors.forename: Stephen
authors.initials: S
authors.lastname: Husbands
authors.forename: David J
authors.initials: DJ
authors.lastname: Nutt
authors.forename: Alan L
authors.initials: AL
authors.lastname: Hudson
mesh_terms: D018674:Adrenergic Antagonists / Q000378:metabolism; D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003952:Diagnostic Imaging / Q000379:methods; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D051379:Mice; D011485:Protein Binding / Q000502:physiology; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology
chemical_list: D018674:Adrenergic Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D018341:Receptors, Adrenergic, alpha-2