Serotonin transporter polymorphisms (SLC6A4 insertion/deletion and rs25531) do not affect the availability of 5-HTT to [11C] DASB binding in the living human brain.

Studies in vitro suggest that the expression of the serotonin transporter (5-HTT) is regulated by polymorphic variation in the promoter region of the 5-HTT gene (5-HTTLPR); however, results from human brain imaging studies examining the relation between 5-HTT genotype and 5-HTT radioligand binding in vivo have been inconsistent. This inconsistency could reflect small participant numbers or the use of sub-optimal radiotracer for measuring the 5-HTT. We used positron emission tomography in conjunction with the selective 5-HTT ligand [(11)C] DASB to examine the availability of the 5-HTT in seven brain regions in 63 healthy European caucasian volunteers who were genotyped for short (S) and long (L) variants (SLC6A4 and rs25531) of the 5-HTTLPR. [(11)C] DASB binding potential was not influenced by the allelic status of participants whether classified on a biallelic or triallelic basis in any of the regions studied. Our PET findings, in a relatively large sample with a near optimal radiotracer, suggest that 5-HTTLPR polymorphic variation does not affect the availability of 5-HTT to [(11)C] DASB binding in adult human brain. The reported impact of 5-HTTLPR polymorphic variation on emotional processing and vulnerability to depression are more likely therefore to be expressed through effects exerted during neurodevelopment.

SPECT imaging of the benzodiazepine receptor: feasibility of in vivo potency measurements from stepwise displacement curves.

Iodine-123-labeled Ro 16-0154 is a high affinity, reversibly binding radiotracer for the benzodiazepine (BZ) receptor. Brain uptake of this radioligand was relatively stable and showed high ratios of specific-to-nonspecific uptake, with greater than 90% displaced by intravenous administration of BZ receptor agents. Repeated injections of increasing doses of each of five BZ drugs (Ro 16-0154, Ro 15-1788, clonazepam, alprazolam, and diazepam) yielded stepwise displacement curves, which were analyzed to measure the in vivo potencies of these agents. The relatively long half-life of 123I and the stable biologic uptake of the radiotracer allowed such potency estimations in just one experiment following a single injection of radioligand. The in vivo potencies of these five agents were highly correlated with their affinities for the BZ receptor determined with in vitro homogenate binding. A single crystal probe provided potency measurements virtually identical to simultaneously performed SPECT imaging studies. In conclusion, stepwise displacement by agents administered following the injection of the radioligand 123I-Ro 16-0154 provided a reliable means of measuring the in vivo potencies of BZ receptor agents. This in vivo determination may predict the clinical potency of BZ drugs than in vitro homogenate estimations, because the in vivo measure provides the summed effects of receptor affinity, plasma protein binding, penetration of the blood-brain barrier, and metabolism of the displacing agent.