Radiosynthesis and evaluation of 11C-CIMBI-5 as a 5-HT2A receptor agonist radioligand for PET.
PET brain imaging of the serotonin 2A (5-hydroxytryptamine 2A, or 5-HT(2A)) receptor has been widely used in clinical studies, and currently, several well-validated radiolabeled antagonist tracers are used for in vivo imaging of the cerebral 5-HT(2A) receptor. Access to 5-HT(2A) receptor agonist PET tracers would, however, enable imaging of the active, high-affinity state of receptors, which may provide a more meaningful assessment of membrane-bound receptors. In this study, we radiolabel the high-affinity 5-HT(2A) receptor agonist 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-[(11)C-OCH(3)]methoxybenzyl)ethanamine ((11)C-CIMBI-5) and investigate its potential as a PET tracer.


METHODS
The in vitro binding and activation at 5-HT(2A) receptors by CIMBI-5 was measured with binding and phosphoinositide hydrolysis assays. Ex vivo brain distribution of (11)C-CIMBI-5 was investigated in rats, and PET with (11)C-CIMBI-5 was conducted in pigs.


RESULTS
In vitro assays showed that CIMBI-5 was a high-affinity agonist at the 5-HT(2A) receptor. After intravenous injections of (11)C-CIMBI-5, ex vivo rat studies showed a specific binding ratio of 0.77 ± 0.07 in the frontal cortex, which was reduced to cerebellar levels after ketanserin treatment, thus indicating that (11)C-CIMBI-5 binds selectively to the 5-HT(2A) receptor in the rat brain. The PET studies showed that the binding pattern of (11)C-CIMBI-5 in the pig brain was in accordance with the expected 5-HT(2A) receptor distribution. (11)C-CIMBI-5 gave rise to a cortical binding potential of 0.46 ± 0.12, and the target-to-background ratio was similar to that of the widely used 5-HT(2A) receptor antagonist PET tracer (18)F-altanserin. Ketanserin treatment reduced the cortical binding potentials to cerebellar levels, indicating that in vivo (11)C-CIMBI-5 binds selectively to the 5-HT(2A) receptor in the pig brain.


CONCLUSIONS
(11)C-CIMBI-5 showed a cortex-to-cerebellum binding ratio equal to the widely used 5-HT(2A) antagonist PET tracer (18)F-altanserin, indicating that (11)C-CIMBI-5 has a sufficient target-to-background ratio for future clinical use and is displaceable by ketanserin in both rats and pigs. Thus, (11)C-CIMBI-5 is a promising tool for investigation of 5-HT(2A) agonist binding in the living human brain.
Ettrup
Anders
A
Neurobiology Research Unit and Center for Integrated Molecular Brain Imaging, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. ettrup@nru.dk
Palner
Mikael
M
Gillings
Nic
N
Santini
Martin A
MA
Hansen
Martin
M
Kornum
Birgitte R
BR
Rasmussen
Lars K
LK
Någren
Kjell
K
Madsen
Jacob
J
Begtrup
Mikael
M
Knudsen
Gitte M
GM
D000588:Amines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001596:Benzylamines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004118:Dimethoxyphenylethylamine / Q000031:analogs & derivatives; D005260:Female; D007275:Injections, Intravenous; D007650:Ketanserin / Q000494:pharmacology; D007700:Kinetics; D010627:Phenethylamines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013552:Swine
D000588:Amines; D001596:Benzylamines; D004118:Dimethoxyphenylethylamine; D010627:Phenethylamines; D011849:Radioactive Tracers; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists; C554181:2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-methoxybenzyl)ethanamine; D007650:Ketanserin