Abstract
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Objectives For 18 kDa translocator protein (TSPO), the affinities of most second generation PET ligands but probably not the prototypical agent PK 11195, are considerably sensitive to the single nucleotide polymorphism rs6971. We synthesized numerous new analogs of PK 11195 and selected O-methyl-(R)-N-sec-butyl-4-(2-chlorophenyl)-N-methylquinazoline-2-carboxamide (ER176) to test in human subjects because it showed little sensitivity to the polymorphism when tested in vitro with tritiated radioligand binding to homogenates of human brain and of white blood cells (1). Its in vitro ratio of affinities for high (HABs) and low affinity binders (LABs) was 1.3 : 1. The aim of this study is to determine whether the in vivo sensitivity of [11C]ER176 in human subjects is similar to that measured in vitro.
Methods Nine healthy controls consisting of 2 females and 1 male each for HAB, MAB (mixed affinity binder), and LAB were studied with whole-body PET imaging for 120 min after a bolus injection of [11C]ER176. Tracer uptake was evaluated by area under the time-radioactivity curves from 15 to 120 min post-injection derived from volumes of interest placed on each organ with visible tracer uptake.
Results [11C]ER176 distributed, as expected, to brain and peripheral organs rich in TSPO. The uptake in TSPO-rich organs, including brain, lungs, heart, spleen, and kidneys, showed a clear and dose-dependent sensitivity to genotype. For example, uptake of lungs in LABs (97 ± 15 SUV • min) was ~60% and in MABs (173 ± 67) was ~30% of that in HABs (243 ± 31).
Conclusions The whole body distribution of [11C]ER176 reflected that for TSPO, but it showed significant sensitivity to the genotype rs6971, which was not expected from in vitro studies. The cause of this discrepancy is unknown, but may involve in vivo protein-protein interactions that are disrupted by tissue homogenization or other in vitro conditions.
Research Support NIMH Intramural Research Program