Radiosynthesis and Evaluation of 11C-CIMBI-5 as a 5-HT2A Receptor Agonist Radioligand for PET
Anders Ettrup, Mikael Palner, Nic Gillings, Martin A. Santini, Martin Hansen, Birgitte Rahbek Kornum, Lars K. Rasmussen, Kjell Någren, Jacob Madsen, Mikael Begtrup, Gitte M. Knudsen
Journal of Nuclear Medicine October 18, 2010 DOI: 10.2967/jnumed.109.074021 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Rats and pigs |
| Interventions | (11)C-CIMBI-5 ketanserin |
| Topics | Serotonin |
| Keywords | Radioligand Agonist Receptor Radiosynthesis In vivo Biochemistry |
| Citations | 50 |
| Key points | (11)C-CIMBI-5 showed selective binding to the 5-HT2A receptor in rat and pig brains with a target-to-background ratio similar to the antagonist tracer (18)F-altanserin. |
Abstract
UNLABELLED: 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.
Conclusion: (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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 14
- Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs). Neuropharmacology December 1, 2015
- Effects of the hallucinogen 2,5-dimethoxy-4-iodophenethylamine (2C-I) and superpotent N-benzyl derivatives on the head twitch response. Neuropharmacology February 1, 2014
- Pharmacology and Toxicology of N-Benzylphenethylamine ("NBOMe") Hallucinogens. Current Topics in Behavioral Neurosciences 2017
- Structure–activity relationships of serotonin 5‐HT2Aagonists Wiley Interdisciplinary Reviews Membrane Transport and Signalling February 28, 2012
- NBOMes–Highly Potent and Toxic Alternatives of LSD Frontiers in Neuroscience February 26, 2020
and 9 more in the library