Kinetic analysis of [¹¹C]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 retention pattern. This study investigates the impulse response function of |¹¹C|(+)McN5652, a radioligand used for positron emission tomography (PET) imaging of the serotonin transporter (SERT) in the brain. Dynamic PET studies were performed in eight healthy volunteers injected with |¹¹C|(+)McN5652 and subsequently with its pharmacologically inactive enantiomer |¹¹C|(-)McN5652. The impulse response function was calculated by deconvolution analysis of regional time-activity curves, and its peak value (f(max)), its retention value at 75 minutes (f(T)), and its normalized retention (f(rel) = f(T)/f(max)) were obtained. Alternatively, compartmental models were applied to calculate the apparent total distribution volume (DV(T)) and its specific binding component (DV(S)). Both the noncompartmental (F(T), f(rel)) and the compartmental parameters (DV) were investigated with and without correction for nonspecific binding by simple subtraction of the corresponding value obtained with [¹¹C](-)McN5652. The impulse response function obtained by deconvolution analysis demonstrated high tracer extraction followed by a slow decline in the form of a monoexponential function. Statistical analysis revealed that the best compartmental model in terms of analysis of variance F and condition number of the parameter variance-covariance matrix was the one that was based on a single tissue compartment with parameters k₁ and k₂ and that also included the parameter of regional cerebral blood volume (BV). The parameter f(rel) demonstrated low between-subject variance (coefficient of variation [CV] = 19%), a midbrain to cerebellum ratio of 1.85, and high correlation with the known density of SERT (r = 0.787 where r is the coefficient of linear correlation between the parameter and the known density of SERT). 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 logarithmic 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 noncompartmental f(rel) with the known density of SERT, and the midbrain to cerebellum ratio was only 1.5 (uncorrected) and 1.8 (corrected). At the expense of increasing variance, the correlation was increased after correction for nonspecific binding using the inactive enantiomer (r = 0.694; CV = 22%). These results indicate that the kinetics of [¹¹C](+)McN5652 can best be described by a one-tissue compartment model with three parameters (k₁, k₂, and BV), and that both the noncompartmental parameter f(rel) and the compartmental distribution volumes have the potential for quantitative estimation of the density of SERT. Further validation of the radioligand in experimental and clinical situations is warranted.