Measuring SSRI occupancy of SERT using the novel tracer [123I]ADAM:: a SPECT validation study

Purpose: Serotonergic brain regions play a crucial role in the modulation of emotion, and serotonergic dysfunction may contribute to several neurological disorders. [I-123]ADAM is a novel SPECT tracer which binds with high affinity to serotonin transporters (SERT). The objective of this study was to compare different methods for the quantification of tracer binding and to develop a simplified single-scan protocol for this tracer, as well as to investigate its potential for characterisation of the transporter occupancy versus plasma concentration curve of a selective serotonin re-uptake inhibitor (SSRI). Methods: Dynamic SPECT scans were performed on 16 healthy volunteers after administration of similar to 150 MBq [I-123]ADAM. Data were acquired from the time of injection until <= 5.5 h after injection in 30- or 45-min sessions. Each subject was scanned twice: with and without pre-treatment with the SSRI citalopram in various dosage regimens. The plasma concentration of citalopram (C-p) was determined from venous samples. Images were reconstructed by filtered back-projection with scatter and attenuation correction. Tracer binding was quantified for midbrain, striatum and thalamus using cerebellum as a reference region. Quantification was done by kinetic modelling, graphical analysis and multi-linear regression, as well as by the ratio method, with binding potential (BP2) as the outcome measure. The SERT occupancy by citalopram was determined relative to the baseline scan for each subject, and the occupancy versus C-p curve was fitted with the E-max model. Results: The highest binding of [I-123]ADAM was in midbrain (mean baseline BP2 +/- SD=1.31 +/- 0.29), with lower binding in thalamus (0.79 +/- 0.16) and striatum (0.66 +/- 0.13). There was good agreement between BP2 values obtained by different quantification methods. Using the ratio method, the best agreement with kinetic modelling was obtained with data from the time interval [200,260] min after injection. The fitting of the midbrain occupancy curve yielded a maximum occupancy of 84% and a plasma concentration required to reach 50% of the maximum of 2.5 ng/ml, with a goodness-of-fit variability of 13% (SD). Conclusion: Binding of [I-123]ADAM to SERT in midbrain can be quantified with a single scan starting 200 min after injection. However, the variability of estimated occupancy values may be too high for critical assessment of occupancy of SERT by SSRI.