Receptor subtype distribution from PET occupancy studies: Novel analysis of maximum occupancy images using a selective drug and a non-selective tracer.

Abstract

The Lassen plot filter (LPF) is a novel quantitative approach for generating voxel-level parametric images of half maximal effective concentration (EC 50 ) and maximum occupancy ( Occ max ) from PET brain occupancy data. We applied LPF to an occupancy study of a 5HT 6 selective antagonist, PF05212377 (SAM760) using the non-selective 5HT 6 /5HT 2A tracer, [ 11 C]GSK215083. We now introduced the occupancy derived B max ratio (ODBR) as a new parameter reflecting receptor density ratios in vivo. Ten healthy subjects underwent baseline, post-drug, and washout PET scans after single oral doses (2-60 mg). LPF-derived occupancy images were produced in the striatum, yielding Occ max values of 0.74 in the caudate and 0.87 in the putamen. The ODBR for 5HT 2A receptors was calculated from incomplete occupancy (1 - Occ max ) and binding potential ratios (ODBR = 2.88; B max caudate (5HT 2A )/ B max putamen (5HT 2A )). This result is consistent with published postmortem B max ratio (1.50-2.41). In general, our approach allows estimation when occupancy studies are performed with a selective drug and a non-selective tracer.