Comparative Evaluation in Nonhuman Primates of Five PET Radiotracers for Imaging the Serotonin Transporters: [11C]McN 5652, [11C]ADAM, [11C]DASB, [11C]DAPA, and [11C]AFM

Abstract

The recent introduction of a number of new radiotracers suitable forimaging the serotonin transporters (SERT) has radically changed thefield of SERT imaging. Whereas, until recently, only one selectiveSERT radiotracer was available ([\chm{^{11}}C]McN 5652) for SERTimaging with positron emission tomography (PET), several new C-11-labeledradiotracers of the -dimethyl-2-(arylthio)benzylamine class havebeen described as appropriate imaging agents for the SERT. The aimof this study was to conduct a comparative evaluation of four ofthe most promising agents in this class ([\chm{^{11}}C]ADAM, [\chm{^{11}}C]DASB,[\chm{^{11}}C]DAPA, and [\chm{^{11}}C]AFM) with the reference tracer[\chm{^{11}}C]McN 5652 under standardized experimental conditions.This evaluation included in vitro measurements of affinity and lipophilicity,and in vivo PET imaging experiments in baboons. In vitro, DASB displayedsignificantly lower affinity for SERT than the other four tracers.In the blood, [\chm{^{11}}C]DASB and [\chm{^{11}}C]AFM display fasterclearance and higher free fractions. Brain uptake was analyzed withkinetic modeling using a one-tissue compartment model and the metabolite-correctedarterial input function. The kinetic uptake of [\chm{^{11}}C]DASBwas significantly faster compared with the other compounds, and thescan duration required to derive time-independent estimates of regionaldistribution volumes was shorter. [\chm{^{11}}C]DAPA exhibited theslowest brain kinetic. Regional-specific-to-nonspecific equilibriumpartition coefficient (V3") was the highest for [\chm{^{11}}C]AFM,followed by [\chm{^{11}}C]DASB and [\chm{^{11}}C]DAPA, which in turnprovided higher V3" values than [\chm{^{11}}C]ADAM and [\chm{^{11}}C]McN5652. From these experiments, two ligands emerged as superior radiotracersthat provide a significant improvement over [\chm{^{11}}C]McN 5652for PET imaging of SERT: [\chm{^{11}}C]DASB, because it enables themeasurement of SERT availability in a shorter scanning time, and[\chm{^{11}}C]AFM, because its higher signal-to-noise ratios providea more reliable measurement of SERT availability in brain regionswith relatively low density of SERT, such as in the limbic system.