TY - JOUR
T1 - Radiosynthesis and in vivo evaluation of novel radioligands for PET imaging of cerebral 5-HT7 receptors
AU - Hansen, Hanne D
AU - Herth, Matthias M
AU - Ettrup, Anders
AU - Andersen, Valdemar L
AU - Lehel, Szabolcs
AU - Dyssegaard, Agnete
AU - Kristensen, Jesper Langgaard
AU - Knudsen, Gitte M
PY - 2014/4/1
Y1 - 2014/4/1
N2 - The serotonin (5-hydroxytryptamine [5-HT]) 7 receptor (5-HT7) is the most recently discovered 5-HT receptor, and its physiologic and possible pathophysiologic roles are not fully elucidated. So far, no suitable 5-HT 7 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-HT7 PET radioligands in the pig brain. The 5-HT7 distribution in the postmortem pig brain is also assessed. Methods: In vitro autoradiography with the 5-HT7 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-HT7 binding distribution. Radiolabeling of 5-HT7 selective compounds was performed in an automated synthesis module in which we conducted either palladiummediated 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-HT7 was investigated by intravenous administration of SB-269970 before a second PET scan. Results: High 5-HT 7 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-HT7 distribution, but the tracer kinetics of 11C-Cimbi- 717 were faster than 11C-Cimbi-712. Both radioligands were specific for 5-HT7, 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 5 6) were calculated in the thalamus. Conclusion: Both 11C-Cimbi- 712 and 11C-Cimbi-717 generated a specific binding in accordance with 5-HT7 distribution and are potential PET radioligands for 5-HT 7. 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-HT 7 binding in the living human brain.
AB - The serotonin (5-hydroxytryptamine [5-HT]) 7 receptor (5-HT7) is the most recently discovered 5-HT receptor, and its physiologic and possible pathophysiologic roles are not fully elucidated. So far, no suitable 5-HT 7 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-HT7 PET radioligands in the pig brain. The 5-HT7 distribution in the postmortem pig brain is also assessed. Methods: In vitro autoradiography with the 5-HT7 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-HT7 binding distribution. Radiolabeling of 5-HT7 selective compounds was performed in an automated synthesis module in which we conducted either palladiummediated 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-HT7 was investigated by intravenous administration of SB-269970 before a second PET scan. Results: High 5-HT 7 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-HT7 distribution, but the tracer kinetics of 11C-Cimbi- 717 were faster than 11C-Cimbi-712. Both radioligands were specific for 5-HT7, 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 5 6) were calculated in the thalamus. Conclusion: Both 11C-Cimbi- 712 and 11C-Cimbi-717 generated a specific binding in accordance with 5-HT7 distribution and are potential PET radioligands for 5-HT 7. 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-HT 7 binding in the living human brain.
U2 - 10.2967/jnumed.113.128983
DO - 10.2967/jnumed.113.128983
M3 - Journal article
C2 - 24566002
SN - 0161-5505
VL - 55
SP - 640
EP - 646
JO - The Journal of Nuclear Medicine
JF - The Journal of Nuclear Medicine
IS - 4
ER -