TY - JOUR T1 - Radiosynthesis and In Vivo Evaluation of Novel Radioligands for PET Imaging of Cerebral 5-HT<sub>7</sub> Receptors JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 640 LP - 646 DO - 10.2967/jnumed.113.128983 VL - 55 IS - 4 AU - Hanne D. Hansen AU - Matthias M. Herth AU - Anders Ettrup AU - Valdemar L. Andersen AU - Szabolcs Lehel AU - Agnete Dyssegaard AU - Jesper L. Kristensen AU - Gitte M. Knudsen Y1 - 2014/04/01 UR - http://jnm.snmjournals.org/content/55/4/640.abstract N2 - The serotonin (5-hydroxytryptamine [5-ΗΤ]) 7 receptor (5-HT7R) is the most recently discovered 5-HT receptor, and its physiologic and possible pathophysiologic roles are not fully elucidated. So far, no suitable 5-HT7R PET radioligand is available, thus limiting the investigation of this receptor in the living brain. Here, we present the radiosynthesis and in vivo evaluation of Cimbi-712 (3-{4-[4-(4-methylphenyl)piperazine-1-yl]butyl}p-1,3-dihydro-2H-indol-2-one) and Cimbi-717 (3-{4-[4-(3-methoxyphenyl)piperazine-1-yl]butyl}-1,3-dihydro-2H-indol-2-one) as selective 5-HT7R PET radioligands in the pig brain. The 5-HT7R distribution in the postmortem pig brain is also assessed. Methods: In vitro autoradiography with the 5-HT7R selective radioligand 3H-labeled (R)-3-(2-(2-(4-methylpiperidin-1-yl)ethyl)pyrrolidine-1-sulfonyl)phenol (SB-269970) was performed on pig brain sections to establish the 5-HT7R binding distribution. Radiolabeling of 5-HT7R selective compounds was performed in an automated synthesis module in which we conducted either palladium-mediated cross coupling (11C-Cimbi-712) or conventional O-methylation (11C-Cimbi-717) using 11C-MeI and 11C-MeOTf, respectively. After intravenous injection of the radioligands in Danish Landrace pigs, the in vivo brain distribution of the ligands was studied. Specific binding of 11C-Cimbi-712 and 11C-Cimbi717 to 5-HT7R was investigated by intravenous administration of SB-269970 before a second PET scan. Results: High 5-HT7R density was found in the thalamus and cortical regions of the pig brain by autoradiography. The radiosynthesis of both radioligands succeeded after optimization efforts (radiochemical yield, ∼20%–30% at the end of synthesis). Time–activity curves of 11C-Cimbi-712 and 11C-Cimbi-717 showed high brain uptake and distribution according to 5-HT7R distribution, but the tracer kinetics of 11C-Cimbi-717 were faster than 11C-Cimbi-712. Both radioligands were specific for 5-HT7R, as binding could be blocked by pretreatment with SB-269970 for 11C-Cimbi-717 in a dose-dependent fashion. For 11C-Cimbi-717, nondisplaceable binding potentials of 6.4 ± 1.2 (n = 6) were calculated in the thalamus. Conclusion: Both 11C-Cimbi-712 and 11C-Cimbi-717 generated a specific binding in accordance with 5-HT7R distribution and are potential PET radioligands for 5-HT7R. 11C-Cimbi-717 is the better candidate because of the more reversible tracer kinetics, and this radioligand showed a dose-dependent decline in cerebral binding after receptor blockade. Thus, 11C-Cimbi-717 is currently the most promising radioligand for investigation of 5-HT7R binding in the living human brain. ER -