Association between triallelic polymorphism of the serotonin transporter and [18F]MPPF binding potential at 5-HT1A receptors in healthy subjects.

Previous [(11)C]WAY100-635 PET studies have demonstrated that the short (S) and long (L) alleles of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) were associated with distinct patterns of 5-HT(1A) receptor distribution in human. However, these studies reported discordant findings and did not take into account the recent description of two functional variants of the L allele (L(A)/L(G)). To further explore this issue, we investigated the triallelic functional polymorphism of the 5-HTTLPR in 38 healthy volunteers who underwent a [(18)F]MPPF PET study of 5-HT1A receptors. We used a simplified reference tissue model to generate parametric images of [(18)F]MPPF binding potential (BP(ND)), and compared these data among the different genotypes using statistical parametric mapping and region of interest of the raphe nuclei. Homozygote carriers of the S allele demonstrated greater [(18)F]MPPF BP(ND) than carriers of the L(A) allele, but this association was only found in women. Differences in [(18)F]MPPF BP(ND) between women with and without L(A) allele were observed over large clusters encompassing the right and left temporal lobes, cingulate and perisylvian regions, as well as the right precuneus and frontal dorso-lateral cortex, and the left orbitofrontal cortex. In contrast, no difference was found between groups in the raphe nuclei. The greater [(18)F]MPPF BP(ND) observed in women homozygote carriers of the S allele could either reflect a greater 5-HT1A receptor density or a lower extracellular concentration of 5-HT. Our data suggest that any future PET studies of 5-HT1A receptors should incorporate the 5-HTTLPR polymorphism status of the population studied.