KINETIC EVALUATION OF POSITRON-EMITTING MUSCARINIC RECEPTOR LIGANDS EMPLOYING DIRECT INTRACAROTID INJECTION

The development and characterization of new receptor ligands for in vi vo binding assays are often both lengthy and expensive. It is therefor e desirable to predict the suitability of a ligand early in the proces s of its evaluation. In the present study, compartmental analysis foll owing intracarotid ligand injection in the monkey is used to evaluate the in vivo kinetics of the muscarinic cholinergic receptor antagonist s [C-11]tropanyl benzilate ([C-11]TRB) and [C-11]N-methylpiperidyl ben zilate ([C-11]NMPB). Animals were implanted with chronic subcutaneous access ports and indwelling catheters with tips located in the common carotid artery,just proximal to its bifurcation. The external carotid artery was ligated to ensure selective tracer delivery through the int ernal carotid artery to the brain. Positron emission tomography was us ed to measure brain tissue time-activity curves following tracer injec tions. CBF was estimated from the clearance of [O-15]H2O, and receptor ligand distributions were analyzed according to a physiologic model c onsisting of an intravascular compartment and nonspecific plus free an d receptor-bound tissue ligand compartments, In [C-11]TRB studies, mar ked reductions in the forward ligand-receptor binding rate and in both the total and the specific binding tissue-to-plasma volumes of ligand distribution were observed after scopolamine receptor blockade or wit h low administered specific activity, Conversely, neither the distribu tion volume of the nonspecific plus free ligand compartment nor the ra te of ligand dissociation from receptor sites was affected. In [C-11]N MPB studies, tissue compartments describing specific binding and nonsa turable components could not be reliably separated. The receptor-relat ed term in this case, the total tissue-to-plasma distribution volume, demonstrated reduction after low specific activity ligand injection. C omparison of the two ligands suggests that NMPB interacts more rapidly with the receptors and has a lower apparent volume of distribution th an does TRB. Thus, NMPB may be the more suitable ligand if accurate es timates of binding dissociation rate are limited by temporal constrain ts or if simplified, one-tissue-compartment analyses are used. The car otid injection method appears promising for the initial evaluation of ligand kinetics, permitting physiologic compartmental analyses without measurement of input functions or chromatography of blood samples.