Loss of cholinergic transmission in the cortex and hippocampus is a characteristic feature of Alzheimer's disease, and visualization of functional cholinergic synapses in the brain with PET could be a useful method for studying this degenerative condition in living humans. We investigated [18F]fluoroethoxybenzovesamicol, (-)-[18F] FEOBV,(-)-(2R,3R)-trans-2-hydroxy-3-(4-phenylpiperidino)-5-(2-[18F ]fluoroethoxy)-1,2,3,4-tetralin, a high affinity positron emitting ligand for the vesicular acetylcholine transporter, as a potential in vivo cholinergic synapse mapping agent. Rodent biodistribution, dosimetry, stereospecificity of biological effects, pharmacologic blocking studies, in vivo rodent brain autoradiography and metabolites were examined. (-)-[18F]FEOBV brain uptake following intravenous injection was robust, with 2.65% dose/brain in mice at 5 min, and the regional localization matched the known distributions of presynaptic cholinergic markers at later times. Both the cholinergic localization and curare-like effects of FEOBV were associated with the "(-)"-enantiomer exclusively. (-)-[18F]FEOBV regional brain distribution in rodents was changed little by pretreatment with haloperidol, (+)-3-PPP, or E-2020, indicating FEOBV, unlike other vesamicol analogs, did not interact in vivo with dopamine or sigma receptor systems. Autoradiography of rat brain 3 h following i.v. injection of (-)-[18F]FEOBV showed high localization in brain areas rich in presynaptic cholinergic elements. Metabolic defluorination in rodents was modest, and analysis of brain tissue following tracer administration found FEOBV as the only extractable radioactive species. (-)-[18F]FEOBV dosimetry calculated from rat data estimate 10 mCi doses can be given to humans. These studies show FEOBV maps cholinergic areas with high specificity in vivo, and may provide a noninvasive means to safely and accurately gauge the functional integrity of cholinergic synapses in man using PET.

Background-Heterogeneous electrophysiological properties, which may be due in part to autonomic innervation, are important in the maintenance of atrial fibrillation (AF). We hypothesized that heterogeneous sympathetic denervation with phenol would create a milieu for sustained AF. Methods and Results-After the determination of baseline inducibility, 15 dogs underwent atrial epicardial phenol application and 11 underwent a sham procedure. After 2 weeks of recovery, the animals had repeat attempts at inducing AF and effective refractory period (ERP) testing. Epicardial maps were obtained to determine local AF cycle lengths. ERPs were determined at baseline and during sympathetic, vagal, and simultaneous vagal/sympathetic stimulation.

Summary: Quantitative estimation of cerebral muscarinic receptors was investigated with the use of the antagonist [llC]tropanyl benzilate ([I I C]TRB) and positron emission tomography (PET). Kinetic modeling alternatives were examined with the goal of identifying an analysis method providing stable receptor measures, yet avoiding biases from inappropriate reductions in model complexity. Dy namic PET scans were performed on six young normal volunteers. Several modeling approaches yielding rela tive receptor density measures were evaluated: (a) a sin gle "late" scan using relative tracer concentration values; (b) a slope estimate from graphic analysis (Patlak plot); (c) a two-compartment, two-parameter model (transport and total ligand distribution volume); (d) a three compartment, two-parameter model using the free + nonspecific distribution volume, DV', fixed to the cere bellar value; (e) an early scan for transport, a fixed value for DV', and a single late scan for the binding rate conIn recent years, positron emission tomography (PET) has been able to provide measures of recep tor density for various neurotransmitter receptor systems in the living human brain. In this study, we investigated the application of kinetic modeling al ternatives for the positron-emitting muscarinic re ceptor antagonist, e IC]tropanyl benzilate (e IC]TRB).Previous attempts at deriving binding information for the muscarinic cholinergic receptor system by Oversimplified approaches (methods 1 and 2) yield a more highly nonlinear relation between the estimated re ceptor density index and the known receptor density than do methods retaining greater model complexity (methods 3-6). However, noise propagation into the receptor mea sure is greater for the more complex methods. Reliable receptor density information can be obtained from kinetic

Summary: Cerebral muscanmc cholinergic receptors were imaged and regionally quantified in vivo in humans with the use of [IIClscopolamine and positron emission tomography. Previous studies in experimental animals have suggested the utility of radiolabeled scopolamine for in vivo measurements, on the bases of its maintained pharmacologic specificity following systemic administra tion and the exclusion of labeled metabolites from the brain. The present studies describe the cerebral distribu tion kinetics of [llC]scopolamine in normal subjects fol lowing intravenous injection. Scopolamine is initially de livered to brain in a perfusion-directed pattern. After 30 to 60 min, activity is lost preferentially from cerebral structures with low muscarinic receptor density including the cerebellum and thalamus. Activity continues to accu mulate throughout a 2 h postinjection period in receptor rich areas including cerebral cortex and the basal ganglia. The late regional concentration of [llClscopolamine does Neuropathologic knowledge of many neurologic and psychiatric illnesses is limited to postmortem observations of changes in specific neuronal popu lations or neurochemical markers. These markers

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