Synthesis and biological evaluation of substituted F-18imidazo1,2-apyridines and F-18pyrazolo1,5-apyrimidines for the study of the peripheral benzodiazepine receptor using positron emission tomography

摘要

The fluoroethoxy and fluoropropoxy substituted 2-(6-chloro-2-phenyl)imidazo1,2-alpyridin-3-yl)-N,N-diethylacetamides 8 (PBR102) and 12 (PBR111) and 2-phenyl-5,7-dimethylpyrazolo1,5-alpyrimidin-3-yl)-N,N-diethylacetamides 15 (PBR099) and 18 (PBR146) were synthesized and found to have high in vitro affinity and selectivity for the peripheral benzodiazepine receptors (PBRs) when compared with the central benzodiazepine receptors (CBRs). The corresponding radiolabeled compounds F-188 F-1812, F-1815, and F-1818 were prepared from their p-toluenesulfonyl precursors in 50-85 radiochemical yield. In biodistribution studies in rats, the distribution of radioactivity of the F-18PBR compounds paralleled the known localization of PBRs. In the olfactory bulbs, where the uptake of radioactivity was higher than in the rest of the brain, PK11195 and Ro 5-4864 were able to significantly inhibit F-1812, while little or no pharmacological action of these established PBR drugs were observed on the uptake of F-188, F-1815, and F-1818 compared to control animals. Hence, F-1812 appeared to be the best candidate for evaluation as an imaging agent for PBR expression in neurodegenerative disorders.