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 (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.


CONCLUSIONS
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.
Parsey
Ramin V
RV
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, New York, USA. rparsey@neuron.cpmc.columbia.edu
Ojha
Ashish
A
Ogden
R Todd
RT
Erlandsson
Kjell
K
Kumar
Dileep
D
Landgrebe
Marguerite
M
Van Heertum
Ronald
R
Mann
J John
JJ
D000814:Aniline Compounds; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000378:metabolism; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008024:Ligands; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008279:Magnetic Resonance Imaging / Q000379:methods; D026901:Membrane Transport Proteins / Q000378:metabolism; D015233:Models, Statistical; D008962:Models, Theoretical; D049268:Positron-Emission Tomography / Q000379:methods*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D020280:Sertraline / Q000737:chemistry; D013440:Sulfides; D013997:Time Factors
C412822:3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile; D000814:Aniline Compounds; D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D008024:Ligands; D026901:Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D013440:Sulfides; D020280:Sertraline