QUANTIFICATION OF MUSCARINIC CHOLINERGIC RECEPTORS WITH [C-11] NMPB AND POSITRON-EMISSION-TOMOGRAPHY - METHOD DEVELOPMENT AND DIFFERENTIATION OF TRACER DELIVERY FROM RECEPTOR-BINDING

Quantification of human brain muscarinic cholinergic receptors was inv estigated with the use of [C-11]N-methyl-4-piperidyl benzylate (NMPB) and positron emission tomography (PET). Whole-brain uptake of NMPB at 90 to 110 minutes after intravenous injection was approximately 10% of the administered dose. The initial cerebral distribution of NMPB corr esponded to the pattern of cerebral perfusion; however, at progressive ly longer postinjection intervals, regional distinctions consistent wi th muscarinic receptor binding were evident: activity at 90 to 110 min utes postinjection was highest in the striatum and cerebral cortex, in termediate in the thalamus and pens, and lowest in the cerebellum. Aft er the development of a chromatographic system for isolation of authen tic [C-11]NMPB in plasma, tracer kinetic modeling was used to estimate receptor binding from the cerebral and arterial plasma tracer time-co urses. Ligand transport rate and receptor-binding estimates were obtai ned with the use of compartmental models and analytical methods of var ying complexity, including a two-parameter pixel-by-pixel-weighted int egral approach and regional least-squares curve-fitting analyses emplo ying both two- and three-compartment model configurations. In test-ret est experiments, precision of the methods and their abilities to disti nguish altered ligand delivery from binding in occipital cortex during an audiovisual presentation were evaluated. Visual stimulation increa sed the occipital blood-to-brain NMPB transport rate by 25% to 46% in estimates arising from the various approaches. Weighted integral analy ses resulted in lowest apparent transport changes and in a concomitant trend toward apparent binding increases during visual activation. The regional least-squares procedures were superior to the pixel-by-pixel method in isolating the effects of altered tracer delivery from recep tor-binding estimates, indicating larger transport effects and unalter ed binding. Precision was best (less than 10% test-retest differences) for the weighted integral analyses and was somewhat lower in the leas t-squares analyses (10-25% differences), The authors conclude that pix el-by-pixel-weighted integral analyses of NMPB distribution introduce transport biases into receptor-binding estimates. Similar confounding effects also are predicted in noncompartmental analyses of delayed rad iotracer distribution. The use of regional nonlinear least-squares fit ting to two-and three-compartment models, although more labor intensiv e, provides accurate distinction of receptor-binding estimates from tr acer delivery with acceptable precision in both intra-and intersubject comparisons.