Pharmacological characterisation of novel α2-adrenoceptor antagonists as potential brain imaging agents
- 作者：Robinson ; Emma S.J. ; Tyacke ; Robin J. ; Finch ; Louise ; Willmott ; Graham ; Husbands ; Stephen ; et. al.
- 关键词：α ; 2-adrenoceptor ; Neuroimaging ; Radioligand binding ; PET and SPECT
- 刊名：Neuropharmacology
- 出版年：2004
- 期刊代码：33_00283908
- 类别：pha
- 出版时间：May, 2004
- 卷：46
- 期：6
- 页码：847-855
- 文件大小：215 K
摘要
Development of suitable imaging ligands to facilitate in vivo characterisation of α2-adrenoceptors has been limited in its success. In the present study, a series of iodinated derivatives and a fluorinated derivative of the classical α2-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 α2-adrenoceptor antagonists 2-methoxy-idazoxan (RX821002) and 2-ethoxy-idazoxan (RX811059). Preliminary studies, investigating their affinities at α2-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 α2-adrenoceptors compared with imidazoline2-binding sites and β-adrenoceptors. Additional functional studies also showed a lack of intrinsic activity at α2-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.