Evaluation of the Serotonin Transporter Ligand ¹²³I-ADAM for SPECT Studies on Humans

Abstract

Imaging serotonin transporters in the living human brain is important in several fields, such as normal psychophysiology, mood disorders, eating disorders, and neurodegenerative disorders. The aim of this study was to compare different kinetic and semiquantitative methods for assessing serotonin transporters using 123 I-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM) in humans: an arterial plasma input model, simplified and Logan reference tissue models, and standardized uptake value ratios. Methods: Nine subjects were scanned with dynamic 123 I-ADAM SPECT (mean age, 31 y; range, 24-43 y), and metabolite-corrected arterial input was measured. Tissue reference models (simplified reference tissue model, Logan reference tissue model, and ratio method) were validated against the outcome of a 1-tissue-compartment model, and performance with decreasing scan length was evaluated. The specificity of 123 I-ADAM binding was investigated in a blocking experiment. Results: Binding estimates from the simplified reference tissue and Logan reference tissue models correlated tightly with full kinetic modeling when based on a 240-or 360-min dynamic acquisition (r 5 0.99); however, there were slight underestimations (3%-5%), especially in high-binding regions. Application of the ratio method to data from 200 to 240 min overestimated specific binding (on average, by 10% 6 28%) and correlated only moderately with estimates from the 1-tissue-compartment model (r 5 0.94). With an acquisition time of 0-120 min, the Logan model still yielded an acceptable outcome when a fixed clearance rate constant (k29) from the cerebellum was applied. Intravenously injected citalopram was not associated with a decrease in cerebellar binding. A lipophilic metabolite that did not seem to bind specifically to serotonin transporter was seen in 2 of 7 subjects. Conclusion: Serotonin transporter binding with 123 I-ADAM SPECT can be assessed with the Logan model based on a 120-min acquisition when a constant k29 is applied. This model, because it allows for more accurate and less biased binding estimates and thus reduces the required sample size, is advantageous over the ratio method used in clinical studies so far. A single blocking experiment supported the use of the cerebellum as a reference region.

In vivo imaging of serotonin transporter occupancy by means of SPECT and [123I]ADAM in healthy subjects administered different doses of escitalopram or citalopram

“…Nevertheless, it has been demonstrated for [ 123 I]ADAM in baboons, that a simple ratio method gave a strong correlation with the full kinetic model (R 2 =0.89); the reference tissue model was only minimally better (R 2 =0.94) (Acton et al 2001). Furthermore, Frokjaer et al (2004) evaluated [ 123 I]ADAM in human subjects, and concluded that the use of the cerebellum as the reference tissue seemed to be warranted.…”

Binding kinetics of 123I[ADAM] in healthy controls: a selective SERT radioligand

“…Apart from the need of accurate determination of plasma metabolites as well as of the free fraction of plasma unmetabolized parent radioligand, arterial sample measurements often appear to be less reproducible (Ichise et al, 2001). In a preliminary SPECT study Frokjaer et al (2004) demonstrated good correlation between full kinetic modelling and a simplified reference tissue model in humans.…”

Overview of Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) Methodologies

“…A recent DATSCAN study has revealed moderately reduced abundance of dopamine transporters in striatum of never-treated patients with schizophrenia (Mateos et al 2007 ) , which seems somewhat at odds with the fi nding of increased effects of amphetamine, noted above. The [ (Frokjaer et al 2008 ) ; SPECT studies with this tracer have revealed increased serotonin transporters in the brainstem of subjects with borderline personality disorder (Koch et al 2007 ) , and have shown the occupancy at serotonin transporters in depressed patients under treatment with citalopram (Herold et al 2006 ) . SPECT tracers for serotonin receptors, as opposed to presynaptic serotonin transporters, are not yet widely available.…”