Comparison of (+)-¹¹C-McN5652 and ¹¹C-DASB as Serotonin Transporter Radioligands Under Various Experimental Conditions

Abstract

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-β-hexahydro-6-[4-(methylthio)phenyl[pyrrolo-[2,1-a]isoquinoline ((+)-¹¹C-McN5652), has been successful in this regard but may have some limitations. Recently, another promising SERT radiotracer, 3-¹¹C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile (¹¹C-DASB), has been described. The purpose of this study was to compare and contrast (+)-¹¹C-McN5652 and ¹¹C-DASB under various experimental conditions. Methods: 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. Results: 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 (+)-¹¹C-McN5652 and ¹¹C-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 (+)-¹¹C-McN5652, ¹¹C-DASB had higher brain activity and a faster washout rate and provided greater contrast between subcortical and cortical brain regions. Conclusion: ¹¹C-DASB and (+)-¹¹C-McN5652 are suitable as PET ligands of the SERT and for detecting MDMA-induced 5-HT neurotoxicity. ¹¹C-DASB may offer some advantages. Additional studies are needed to further characterize the properties and capabilities of both ligands in health and disease.