Metabolite considerations in the in vivo quantification of serotonin transporters using 11C-DASB and PET in humans

Abstract

PET studies of the serotonin (5-hydroxytryptamine, or 5-HT) transporter are increasingly using (11)C-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile (DASB). We noted that the percentage of unmetabolized (11)C-DASB is often lower at 2 min after injection than at 12 min. We hypothesized that this is due to initial "trapping" of the unmetabolized (11)C-DASB compound in the lung, a major 5-HT transporter site and dose-limiting organ. To determine whether binding to an extracranial pool of 5-HT transporters contributes to the lower initial level of unmetabolized (11)C-DASB, we examined the effects of sertraline.

Methods: Eleven healthy volunteers had 2 (11)C-DASB PET scans on the same day, and 6 of the 11 had a third scan after sertraline administration. The unmetabolized (11)C-DASB fraction was measured in arterial plasma as a function of time and was fit with 2 exponentials with no damping, power function damping, or no damping with the first point removed.

Results: Power function damping best fit the data as assessed by visual inspection and residuals and resulted in greater distribution volumes than did no damping with the first point removed. Test-retest reproducibility improved when power function damping was used, as compared with no damping with the first point removed. Oral sertraline raised the 2-min unmetabolized (11)C-DASB percentage.

Conclusion: Measurement and fitting of early metabolism time points improves curve fitting, significantly affects volume-of-distribution determination, and improves test-retest reproducibility. Saturation of lung 5-HT transporters by sertraline prevents the initial trapping of (11)C-DASB. Initial trapping of high-affinity radioligands may be important in the quantification of the binding of other ligands with a high concentration of binding sites in the lungs.