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

PET studies of the serotonin (5-hydroxytryptamine, or 5-HT) transporter are increasingly using ¹¹C-3-amino-4-(2- dimethylaminomethylphenylsulfanyl) benzonitrile (DASB). We noted that the percentage of unmetabolized ¹¹C-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 ¹¹C-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 ¹¹C-DASB, we examined the effects of sertraline. Methods: Eleven healthy volunteers had 2 ¹¹C-DASB PET scans on the same day, and 6 of the 11 had a third scan after sertraline administration. The unmetabolized ¹¹C-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 ¹¹C-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 ¹¹C-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.