Signal separation and parameter estimation in noninvasive dual-tracer PET scans using reference-region approaches

This is the first study to report results from a noninvasive dual-tracer positron emission tomography (PET) in humans not requiring arterial sampling, in which two radiotracers were injected closely in time within the same scan. These studies yield near simultaneous information on two different neuropharmacological systems, providing better characterization of a subject's neurologic condition. The noninvasive dual-tracer approach described in this study is based on the primary assumption that an appropriate bolus plus constant infusion protocol brings the reference tissue of the first radiotracer to steady state before injection of the second tracer. Two methods for separation of time-activity curves (TACs) and parameter estimation were investigated, namely (1) an extrapolation method, in which TACs of the first tracer were extrapolated over total scan duration followed by subtraction from dual-tracer TACs and (2) a simultaneous fitting method, in which reference-region models for both tracers were fitted simultaneously to dual-tracer TACs. Combinations of two reversible tracers ([(11)C]flumazenil and [(11)C]dihydrotetrabenazine) or one reversible and one irreversible tracer ([(11)C]N-methylpiperidinyl propionate) were used. After the dual-tracer scan, a single-tracer (ST) scan using one of the tracers was obtained for comparison of the dual-tracer results. Both approaches provided parameter estimates with intersubject regions-of-interest means typically within 10% of those obtained from ST scans without an appreciable increase in variance.