mcn-5652 and 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile

Pharmacokinetic modelling of dynamic PET data has become an important tool to analyse in-vivo studies in humans and animals. Estimation of the model parameters often requires non-linear regression of an objective function such as weighted least squares. Since the noise properties of the data are not known exactly in practice, several weighting schemes have been proposed. The objective of this study was to evaluate the impact of commonly used weights on neuroreceptor quantification with the simplified reference tissue model (SRTM).. We compared the following weights: uniform, Poisson statistics-based ideal and noisy weights, iterative weighting, and a noise-free approximation of Poisson weights. Ten thousand time-activity curves (TACs) were simulated for several noise levels and the three neuroreceptor PET ligands C-(+)McN5652, C-DASB, and C-raclopride. Each TAC was fitted using weighted non-linear regression of the SRTM. We assessed bias and variation of the parameter estimates as well as quality of fit and parameter distributions.. Results differed substantially between ligands and between model parameters. Best parameter estimates were obtained with the noise-free approximation of Poisson weights. The often-used noisy Poisson weights performed worst for all ligands. Uniform weighting gave acceptable parameter estimates for most setups.. 'Choice of weights' is important in pharmacokinetic neuroreceptor quantification with the SRTM. Weights estimated directly from noisy data should be avoided as they can severely degrade parameter estimation and the statistical power of a study. If the noise characteristic of the data is unknown, uniform weighting is recommended.

Topics: Aniline Compounds; Humans; Isoquinolines; Kinetics; Ligands; Linear Models; Models, Neurological; Neurons; Poisson Distribution; Positron-Emission Tomography; Raclopride; Radiopharmaceuticals; Reference Values; Regression Analysis; Reproducibility of Results; Sulfides

There has been considerable interest in the development of a PET radioligand selective for the serotonin (5-hydroxytryptamine [5-HT]) transporter (SERT) that can be used to image 5-HT neurons in the living human brain. The most widely used SERT radiotracer to date, trans-1,2,3,5,6,10-beta-hexahydro-6-[4-(methylthio)phenyl[pyrrolo-[2,1-a]isoquinoline ((+)-(11)C-McN5652), has been successful in this regard but may have some limitations. Recently, another promising SERT radiotracer, 3-(11)C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile ((11)C-DASB), has been described. The purpose of this study was to compare and contrast (+)-(11)C-McN5652 and (11)C-DASB under various experimental conditions.. Radioligand comparisons were performed in a control baboon, a baboon with reduced SERT density ((+/-)-3,4-methylenedioxymethamphetamine [MDMA] lesion), and a baboon with reduced SERT availability (paroxetine pretreatment). Under each of these experimental conditions, repeated (triplicate) PET studies were performed with each ligand.. Both radiotracers bound preferentially in brain regions known to contain high SERT density. For both ligands, there was a high correlation between the amount of regional brain ligand binding and the known regional brain concentration of SERT. Binding of both ligands was decreased after MDMA neurotoxicity (reduced SERT density), and (+)-(11)C-McN5652 and (11)C-DASB were comparably effective in detecting reduced SERT density after MDMA-induced 5-HT neurotoxicity. Pretreatment with paroxetine dramatically altered the metabolism and kinetics of both tracers and appeared to displace both ligands primarily from regions with high SERT density. Compared with (+)-(11)C-McN5652, (11)C-DASB had higher brain activity and a faster washout rate and provided greater contrast between subcortical and cortical brain regions.. (11)C-DASB and (+)-(11)C-McN5652 are suitable as PET ligands of the SERT and for detecting MDMA-induced 5-HT neurotoxicity. (11)C-DASB may offer some advantages. Additional studies are needed to further characterize the properties and capabilities of both ligands in health and disease.

Topics: Aniline Compounds; Animals; Carbon Radioisotopes; Carrier Proteins; Isoquinolines; Male; Membrane Glycoproteins; Membrane Transport Proteins; Models, Biological; N-Methyl-3,4-methylenedioxyamphetamine; Nerve Tissue Proteins; Papio; Paroxetine; Protein Binding; Radioligand Assay; Radiopharmaceuticals; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Sulfides; Tomography, Emission-Computed