POSITRON EMISSION TOMOGRAPHIC INVESTIGATIONS OF CENTRAL MUSCARINIC CHOLINERGIC RECEPTORS WITH 3 ISOMERS OF [BR-76]BRQNP

We studied the potential of three radiobrominated isomers of BrQNP, (Z (-,-)-[Br-76]BrQNP, E(-,-)[Br-76]BrQNP and E(-,+)-[Br-76]BrQNP), as su itable radioligands for imaging of central muscarinic cholinergic rece ptors in the human brain. These radioligands were stereospecifically p repared by electrophilic radiobromodestannylation of the respective tr ibutylstannyl precursors using no-carrier-added [Br-76]BrNH4 and perac etic acid. Preliminary pharmacological characterizations were determin ed by biodistribution, autoradiography, competition, displacement and metabolite studies in rats. The (-,-)-configuration presented importan t specific uptakes in brain muscarinic cholinergic receptor (mAChR)-ri ch structures and in heart, low metabolization rates and an apparent M -2 selectivity. The (-,+)-configuration revealed more rapid clearance, lower uptake, a higher metabolization rate and an apparent M-1 select ivity. Reversibility of the binding was confirmed for the three radiot racers. Positron emission tomography in the living baboon brain reveal ed high and rapid uptake in the brain and accumulation in the mAChR-ri ch structures studied. At 30 min p.i., the E(-,-)-radiotracer reached a plateau in cortex, pens and thalamus with concentrations of 29%, 24% and 19% respectively. [Br-76]BrQNP also accumulated in these structur es, reaching a maximal uptake (27% ID/1) in the cortex 2 h p.i. At 5 m in p.i. a plateau (17% ID/1) was only observed in the cortex for the E (-,+)-[Br-76]BrQNP; by contrast, the other structures showed slow wash out. After 3 weeks, the (-,-)-radiotracers were studied in the same ba boon pretreated with dexetimide (1 mg/kg), a well-known muscarinic ant agonist. In all the mAChR structures, the highly reduced uptake observ ed after this preloading step indicates that these radiotracers specif ically bind to muscarinic receptors. Z(-,-)-[Br-76]BrQNP, which is dis placed in higher amounts from M-2 mAChR-enriched structures, reveals a n M-2 affinity. The two isomers having the (-,-)-configuration are pot ential probes for investigating central muscarinic receptors. The abso lute configuration on the acetate chiral centre influences their musca rinic subtype selectivity and the cis-trans isomerism of the vinyl moi ety affects their specific fixation.