Synthesis and biological evaluation of substituted [18F]imidazo[1,2-a]pyridines and [18F]pyrazolo[1,5-a]pyrimidines for the study of the peripheral benzodiazepine receptor using positron emission tomography.
The fluoroethoxy and fluoropropoxy substituted 2-(6-chloro-2-phenyl)imidazo[1,2- a]pyridin-3-yl)- N, N-diethylacetamides 8 (PBR102) and 12 (PBR111) and 2-phenyl-5,7-dimethylpyrazolo[1,5- a]pyrimidin-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 [ (18)F] 8 [ (18)F] 12, [ (18)F] 15, and [ (18)F] 18 were prepared from their p-toluenesulfonyl precursors in 50-85% radiochemical yield. In biodistribution studies in rats, the distribution of radioactivity of the [ (18)F]PBR 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 [ (18)F] 12, while little or no pharmacological action of these established PBR drugs were observed on the uptake of [ (18)F] 8, [ (18)F] 15, and [ (18)F] 18 compared to control animals. Hence, [ (18)F] 12 appeared to be the best candidate for evaluation as an imaging agent for PBR expression in neurodegenerative disorders.
Radiopharmaceuticals Research Institute, Australian Nuclear Science and Technology Organisation, PMB 1 Menai NSW 2234, Sydney, Australia.
Christopher J R
CJ
Fookes
Tien Q
TQ
Pham
Filomena
F
Mattner
Ivan
I
Greguric
Christian
C
Loc'h
Xiang
X
Liu
Paula
P
Berghofer
Rachael
R
Shepherd
Marie-Claude
MC
Gregoire
Andrew
A
Katsifis
D000818:Animals; D005269:Femur / Q000187:drug effects; D005462:Fluorine Radioisotopes; D007093:Imidazoles / Q000737:chemistry*; D008024:Ligands; D015394:Molecular Structure; D009830:Olfactory Bulb / Q000187:drug effects; D009928:Organ Specificity / Q000187:drug effects; D049268:Positron-Emission Tomography; D011720:Pyrazoles / Q000737:chemistry*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D013329:Structure-Activity Relationship
D005462:Fluorine Radioisotopes; D007093:Imidazoles; D008024:Ligands; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D011963:Receptors, GABA-A; C031280:pyrazole; C029899:imidazole