MUSCARINIC CHOLINERGIC RECEPTOR MEASUREMENTS WITH [F-18] FP-TZTP - CONTROL AND COMPETITION STUDIES

[[F-18]Fluoropropyl-TZTP (FP-TZTP) is a subtype-selective muscarinic c holinergic Ligand with potential suitability for studying Alzheimer's disease. Positron emission tomography studies in isofluorane-anestheti zed rhesus monkeys were performed to assess the in vivo behavior of th is radiotracer. First, control studies (n = 11) were performed to char acterize the tracer kinetics and to choose an appropriate model using a metabolite-corrected arterial input function. Second, preblocking st udies (n = 4) with unlabeled FP-TZTP were used to measure nonspecific binding. Third, the sensitivity of [F-18]FP-TZTP binding to changes in brain acetylcholine (ACh) was assessed by administering physostigmine , an acetylcholinesterase (AChE) inhibitor, by intravenous infusion (1 00 to 200 mu g.kg(-1).h(-1)) beginning 30 minutes before tracer inject ion (n = 7). Tracer uptake in the brain was rapid with K-1 values of 0 .4 to 0.6 mL.min(-1).mL(-1) in gray matter. A model with one tissue co mpartment was chosen because reliable parameter estimates could not be obtained with a more complex model. Volume of distribution (V) values , determined from functional images created by pixel-by-pixel fitting, were very similar ia cortical regions, basal ganglia, and thalamus, b ut significantly lower (P < 0.01) in the cerebellum consistent with th e distribution of M-2 cholinergic receptors. Preblocking studies with unlabeled FP-TZTP reduced V by 60% to 70% in cortical and subcortical regions. Physostigmine produced a 35% reduction in cortical specific b inding (P < 0.05), consistent with increased ACh competition. The redu ction in basal ganglia (12%) was significantly smaller (P < 0.05), con sistent with its markedly higher AChE activity. These studies indicate that [F-18]FP-TZTP should be useful for the in vivo measurement of mu scarinic receptors with position emission tomography.