Aim
The radiotracer, [123I]ADAM, is a new tool for SPECT-imaging of in-vivo serotonin transporters (SERTs). So far, no study describing the kinetics of [123I]ADAM, its metabolites, or the selectivity of the ligand in humans has been published. The aims of this study were to evaluate quantification of [123I]ADAM with simplified models against full kinetic modeling, to investigate [123I]ADAM metabolites, and to validate the selectivity of [123I]ADAM binding through a SSRI blocking experiment.
Material and methods
Six healthy volunteers, 3 men and 3 women, with a median age of 31 years (range 24–43) were included. After IV bolus injection of [123I]ADAM (median dose 260 MBq, range 206–329) dynamic SPECT scanning was conducted over 5.5 hours. Arterial plasma samples were taken and fractions of parent compound and labelled metabolites were determined by high performance liquid chromotography (HPLC) after solid phase extraction. Starting at 4 hours from injection, five of the subjects received intravenous injection of citalopram (0.25 mg/kg) in order to block specific SERT binding. Due to unacceptable side effects three subjects received a reduced dosage (0.05, 0.07 and 0.11 mg/kg). The side effects were reversed within a few minutes allowing continuation of data acquisition.
Results
Preliminary data analysis in three subjects including 4 brain regions, showed a significant correlation between results from the simplified tissue reference model (STRM) and full kinetic modelling using arterial input: Two-tissue compartment model (2 T)/STRM: r=0.92, graphical analysis/STRM r=0.93. Also, the ratio method correlated well with 2 T (r=0.94), and graphical analysis (r=0.89). Time activity curves of the brain uptake of tracer before and after SSRI blocking showed displacement of tracer in all midbrain regions but not in cerebellum, justifying that cerebellum represents non-specific binding. The time course of fractional unchanged [123I]ADAM varied from subject to subject typically being around 50% at 20 minutes, decreasing to 5–12 % 3–4 hours after injection. A labelled lipophilic compound was found in two subjects. The fraction of this lipophilic compound peaked around 2 hours after injection where it constituted about 13%. The concentration of [123I]ADAM increased following blocking with citalopram whereas the concentration of the lipohilic metabolite remained constant suggesting that this metabolite does not bind to SERTs.
Conclusion
Quantification of SERT with [123I]ADAM is feasible with the simplified models which yields proportional measures to those from full kinetic modeling. Cerebellar activity represents nonspecific binding only and can serve as a reference region. [123I]ADAM metabolism is highly variable and in some subjects labelled lipophilic metabolites can be detected. Based on our data, however, it does not seem that the labelled metabolite binds to SERT. More subjects will be included for the evaluation of quantification models. Further, the stability of [123I]ADAM in full blood as well as in samples prepared for HPLC analysis will be evaluated in order to test whether the lipophilic compound observed truly represents a metabolite.