Muscarinic cholinergic receptor measurements with [18F]FP-TZTP: control and competition studies.
[18F]Fluoropropyl-TZTP (FP-TZTP) is a subtype-selective muscarinic cholinergic ligand with potential suitability for studying Alzheimer's disease. Positron emission tomography studies in isofluorane-anesthetized rhesus monkeys were performed to assess the in vivo behavior of this radiotracer. First, control studies (n = 11) were performed to characterize the tracer kinetics and to choose an appropriate model using a metabolite-corrected arterial input function. Second, preblocking studies (n = 4) with unlabeled FP-TZTP were used to measure nonspecific binding. Third, the sensitivity of [18F]FP-TZTP binding to changes in brain acetylcholine (ACh) was assessed by administering physostigmine, an acetylcholinesterase (AChE) inhibitor, by intravenous infusion (100 to 200 microg x kg(-1) x h(-1)) beginning 30 minutes before tracer injection (n = 7). Tracer uptake in the brain was rapid with K1 values of 0.4 to 0.6 mL x min(-1) x mL(-1) in gray matter. A model with one tissue compartment 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 in cortical regions, basal ganglia, and thalamus, but significantly lower (P < 0.01) in the cerebellum, consistent with the distribution of M2 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 binding (P < 0.05), consistent with increased ACh competition. The reduction in basal ganglia (12%) was significantly smaller (P < 0.05), consistent with its markedly higher AChE activity. These studies indicate that [18F]FP-TZTP should be useful for the in vivo measurement of muscarinic receptors with positron emission tomography.
Positron Emission Tomography Department, National Institutes of Health, Bethesda, Maryland 20892-1180, USA.
R E
RE
Carson
D O
DO
Kiesewetter
E
E
Jagoda
M G
MG
Der
P
P
Herscovitch
W C
WC
Eckelman
D000109:Acetylcholine / Q000378:metabolism; D000758:Anesthesia; D018685:Anesthetics, Inhalation; D000818:Animals; D001667:Binding, Competitive; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002855:Chromatography, Thin Layer; D005462:Fluorine Radioisotopes; D007530:Isoflurane; D007700:Kinetics; D008253:Macaca mulatta; D008959:Models, Neurological; D010830:Physostigmine / Q000494:pharmacology; D011725:Pyridines / Q000493:pharmacokinetics; D011976:Receptors, Muscarinic / Q000378:metabolism*; D013844:Thiazoles / Q000493:pharmacokinetics; D014055:Tomography, Emission-Computed
D018685:Anesthetics, Inhalation; D001798:Blood Proteins; D002800:Cholinesterase Inhibitors; D005462:Fluorine Radioisotopes; D011725:Pyridines; D011976:Receptors, Muscarinic; D013844:Thiazoles; D010830:Physostigmine; C115177:FP-TZTP; D007530:Isoflurane; D000109:Acetylcholine