Kinetic analysis of [C-11]McN5652: A serotonin transporter radioligand

The impulse response function of a radioligand is the most fundamental way to describe its pharmacokinetics and to assess its tissue uptake and retent ion pattern. This study investigates the impulse response function of [C-11 ](+)McN5652, a radioligand used for positron emission tomography (PET) imag ing of the serotonin transporter (SERT) in the brain. Dynamic PET studies w ere performed in eight healthy volunteers injected with [C-11](+)McN5652 an d subsequently with its pharmacologically inactive enantiomer [C-11](-)McN5 652, The impulse response function was calculated by deconvolution analysis of regional time-activity curves, and its peak value (f(max)), its retenti on value at 75 minutes (f(T)), and if, normalized retention (f(rel) = f(T)/ f(max)) were obtained. Alternatively, compartmental models were applied to calculate the apparent total distribution volume (DVT) and its specific bin ding component (DVT). Both the noncompartmental (f(T), f(rel)) and the comp artmental parameters (DV) were investigated with and without correction for nonspecific binding by simple subtraction of the corresponding value obtai ned with [C-11](-)McN5652, The impulse response function obtained by deconv olution analysis demonstrated high tracer extraction followed by a slow dec line in the form of a monoexponential function. Statistical analysis reveal ed that the best compartmental model in terms of analysis of variance F and condition number of the parameter variance-covariance matrix was the one t hat was based on a single tissue compartment with parameters k, and k, and that also included the parameter of regional cerebral blood volume (BV). Th e parameter f(rel) demonstrated low between subject variance (coefficient o f variation [CVI = 19%), a midbrain to cerebellum ratio of 1.85, and high c orrelation with the known density of SEPT (r = 0.787 where r is the coeffic ient of linear correlation between the parameter and the known density of S ERT). After correction for nonspecific binding, f(rel) demonstrated further improvement in correlation (r = 0.814) and midbrain to cerebellum ratio (3 .09). The variance of the distribution volumes was acceptable when the loga rithmic transform InDV was used instead of DV (17% for the three-parameter model), but correlation of this compartmental parameter was slightly less ( r = 0.652 for the three-parameter model) than the correlation of the noncom partmental S,,, with the known density of SEPT, and the midbrain to cerebel lum ratio was only 1.5 (uncorrected) and 1.8 (corrected). At the expense of increasing variance, the correlation was increased after correction for no nspecific binding using the inactive enantiomer (r = 0.694; CV = 22%). Thes e results indicate that the kinetics of [C-11](+)McN5652 can best be descri bed by a one-tissue compartment model with three parameters (k(1,) k(2), an d BV), and that both the noncompartmental parameter f(rel) and the compartm ental distribution volumes have the potential for quantitative estimation o f the density of SERT. Further validation of the radioligand in experimenta l and clinical situations is warranted.