[C-11] TROPANYL BENZILATE BINDING TO MUSCARINIC CHOLINERGIC RECEPTORS- METHODOLOGY AND KINETIC MODELING ALTERNATIVES

Quantitative estimation of cerebral muscarinic receptors was investiga ted with the use of the antagonist [C-11]tropanyl benzilate ([C-11]TRB ) and positron emission tomography (PET). Kinetic modeling alternative s were examined with the goal of identifying an analysis method provid ing stable receptor measures, yet avoiding biases from inappropriate r eductions in model complexity. Dynamic PET scans were performed on six young normal volunteers. Several modeling approaches yielding relativ e receptor density measures were evaluated: (a) a single ''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-co mpartment, two-parameter model using the free + nonspecific distributi on volume, DV', fixed to the cerebellar value; (e) an early scan for t ransport, a fixed value for DV', and a single late scan for the bindin g rate constant; and (f) a three-compartment, three-parameter model. B oth computer simulations and PET scan results indicate all methods pro vide receptor density index measures with the same rank order as in vi tro measures. Oversimplified approaches (methods 1 and 2) yield a more highly nonlinear relation between the estimated receptor density inde x and the known receptor density than do methods retaining greater mod el complexity (methods 3-6). However, noise propagation into the recep tor measure is greater for the more complex methods. Reliable receptor density information can be obtained from kinetic [C-11]TRB PET studie s, with methods 3-5 providing the most appropriate levels of model com plexity for estimates of relative muscarinic receptor density.