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Metabolite Considerations in the In Vivo Quantification of Serotonin Transporters Using ¹¹C-DASB and PET in Humans

¹ Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York; ² Department of Neuroscience, New York State Psychiatric Institute, New York, New York; ³ Department of Biostatistics, Columbia University School of Public Health, New York, New York; and ⁴ Department of Radiology, Columbia University College of Physicians and Surgeons, New York, New York

Correspondence: For correspondence contact: Ramin V. Parsey, MD, PhD, New York State Psychiatric Institute, 1051 Riverside Dr., Box 42, New York, NY 10032. E-mail: rparsey{at}neuron.cpmc.columbia.edu

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.

Key Words: 5-HT • lung • modeling

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