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 Kyhn Rasmussen; Kjell  Någren; Jacob Madsen; Mikael Begtrup; Gitte Moos Knudsen

doi:10.2967/jnumed.109.074021

Radiosynthesis and evaluation of ¹¹C-CIMBI-5 as a 5-HT_2A receptor agonist radioligand for PET

Anders Ettrup, Mikael Palner, Nic Gillings, Martin A Santini, Martin Hansen, Birgitte Rahbek Kornum, Lars Kyhn Rasmussen, Kjell Någren, Jacob Madsen, Mikael Begtrup, Gitte Moos Knudsen

Neuropharm and Genetics

34 Citations (Scopus)

Abstract

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 highaffinity 5-HT_2A receptor agonist 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-[ ¹¹C-OCH₃]methoxybenzyl)ethanamine (¹¹C-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 ¹¹C-CIMBI-5 was investigated in rats, and PET with ¹¹C-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 ¹¹C-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 ¹¹C-CIMBI-5 binds selectively to the 5-HT _2A receptor in the rat brain. The PET studies showed that the binding pattern of ¹¹C-CIMBI-5 in the pig brain was in accordance with the expected 5-HT_2A receptor distribution. ¹¹C-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 ¹⁸F-altanserin. Ketanserin treatment reduced the cortical binding potentials to cerebellar levels, indicating that in vivo ¹¹C-CIMBI-5 binds selectively to the 5-HT_2A receptor in the pig brain. Conclusion: ¹¹C-CIMBI-5 showed a cortex-to-cerebellum binding ratio equal to the widely used 5-HT _2A antagonist PET tracer ¹⁸F-altanserin, indicating that ¹¹C-CIMBI-5 has a sufficient target-to-background ratio for future clinical use and is displaceable by ketanserin in both rats and pigs. Thus, ¹¹C-CIMBI-5 is a promising tool for investigation of 5-HT _2A agonist binding in the living human brain.

Original language	English
Journal	Journal of Nuclear Medicine
Volume	51
Issue number	11
Pages (from-to)	1763-1770
ISSN	0161-5505
DOIs	https://doi.org/10.2967/jnumed.109.074021
Publication status	Published - 1 Nov 2010

Keywords

Faculty of Health and Medical Sciences

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10.2967/jnumed.109.074021

http://jnm.snmjournals.org/content/51/11/1763.full.pdf

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@article{6aa85cb785084eb4a30a0168b365501d,

title = "Radiosynthesis and evaluation of 11C-CIMBI-5 as a 5-HT2A receptor agonist radioligand for PET",

abstract = "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-HT2A receptor. Access to 5-HT2A 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 highaffinity 5-HT2A receptor agonist 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-[ 11C-OCH3]methoxybenzyl)ethanamine (11C-CIMBI-5) and investigate its potential as a PET tracer. Methods: The in vitro binding and activation at 5-HT2A receptors by CIMBI-5 was measured with binding and phosphoinositide hydrolysis assays. Ex vivo brain distribution of 11C-CIMBI-5 was investigated in rats, and PET with 11C-CIMBI-5 was conducted in pigs. Results: In vitro assays showed that CIMBI-5 was a high-affinity agonist at the 5-HT2A receptor. After intravenous injections of 11C-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 11C-CIMBI-5 binds selectively to the 5-HT 2A receptor in the rat brain. The PET studies showed that the binding pattern of 11C-CIMBI-5 in the pig brain was in accordance with the expected 5-HT2A receptor distribution. 11C-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 18F-altanserin. Ketanserin treatment reduced the cortical binding potentials to cerebellar levels, indicating that in vivo 11C-CIMBI-5 binds selectively to the 5-HT2A receptor in the pig brain. Conclusion: 11C-CIMBI-5 showed a cortex-to-cerebellum binding ratio equal to the widely used 5-HT 2A antagonist PET tracer 18F-altanserin, indicating that 11C-CIMBI-5 has a sufficient target-to-background ratio for future clinical use and is displaceable by ketanserin in both rats and pigs. Thus, 11C-CIMBI-5 is a promising tool for investigation of 5-HT 2A agonist binding in the living human brain.",

keywords = "Faculty of Health and Medical Sciences",

author = "Anders Ettrup and Mikael Palner and Nic Gillings and Santini, {Martin A} and Martin Hansen and Kornum, {Birgitte Rahbek} and Rasmussen, {Lars Kyhn} and Kjell N{\aa}gren and Jacob Madsen and Mikael Begtrup and Knudsen, {Gitte Moos}",

note = "Keywords: PET tracer development, agonist, porcine, serotonin receptors",

year = "2010",

month = nov,

day = "1",

doi = "10.2967/jnumed.109.074021",

language = "English",

volume = "51",

pages = "1763--1770",

journal = "The Journal of Nuclear Medicine",

issn = "0161-5505",

publisher = "Society of Nuclear Medicine",

number = "11",

}

TY - JOUR

T1 - Radiosynthesis and evaluation of 11C-CIMBI-5 as a 5-HT2A receptor agonist radioligand for PET

AU - Ettrup, Anders

AU - Palner, Mikael

AU - Gillings, Nic

AU - Santini, Martin A

AU - Hansen, Martin

AU - Kornum, Birgitte Rahbek

AU - Rasmussen, Lars Kyhn

AU - Någren, Kjell

AU - Madsen, Jacob

AU - Begtrup, Mikael

AU - Knudsen, Gitte Moos

N1 - Keywords: PET tracer development, agonist, porcine, serotonin receptors

PY - 2010/11/1

Y1 - 2010/11/1

N2 - 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-HT2A receptor. Access to 5-HT2A 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 highaffinity 5-HT2A receptor agonist 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-[ 11C-OCH3]methoxybenzyl)ethanamine (11C-CIMBI-5) and investigate its potential as a PET tracer. Methods: The in vitro binding and activation at 5-HT2A receptors by CIMBI-5 was measured with binding and phosphoinositide hydrolysis assays. Ex vivo brain distribution of 11C-CIMBI-5 was investigated in rats, and PET with 11C-CIMBI-5 was conducted in pigs. Results: In vitro assays showed that CIMBI-5 was a high-affinity agonist at the 5-HT2A receptor. After intravenous injections of 11C-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 11C-CIMBI-5 binds selectively to the 5-HT 2A receptor in the rat brain. The PET studies showed that the binding pattern of 11C-CIMBI-5 in the pig brain was in accordance with the expected 5-HT2A receptor distribution. 11C-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 18F-altanserin. Ketanserin treatment reduced the cortical binding potentials to cerebellar levels, indicating that in vivo 11C-CIMBI-5 binds selectively to the 5-HT2A receptor in the pig brain. Conclusion: 11C-CIMBI-5 showed a cortex-to-cerebellum binding ratio equal to the widely used 5-HT 2A antagonist PET tracer 18F-altanserin, indicating that 11C-CIMBI-5 has a sufficient target-to-background ratio for future clinical use and is displaceable by ketanserin in both rats and pigs. Thus, 11C-CIMBI-5 is a promising tool for investigation of 5-HT 2A agonist binding in the living human brain.

AB - 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-HT2A receptor. Access to 5-HT2A 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 highaffinity 5-HT2A receptor agonist 2-(4-iodo-2,5-dimethoxyphenyl)-N-(2-[ 11C-OCH3]methoxybenzyl)ethanamine (11C-CIMBI-5) and investigate its potential as a PET tracer. Methods: The in vitro binding and activation at 5-HT2A receptors by CIMBI-5 was measured with binding and phosphoinositide hydrolysis assays. Ex vivo brain distribution of 11C-CIMBI-5 was investigated in rats, and PET with 11C-CIMBI-5 was conducted in pigs. Results: In vitro assays showed that CIMBI-5 was a high-affinity agonist at the 5-HT2A receptor. After intravenous injections of 11C-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 11C-CIMBI-5 binds selectively to the 5-HT 2A receptor in the rat brain. The PET studies showed that the binding pattern of 11C-CIMBI-5 in the pig brain was in accordance with the expected 5-HT2A receptor distribution. 11C-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 18F-altanserin. Ketanserin treatment reduced the cortical binding potentials to cerebellar levels, indicating that in vivo 11C-CIMBI-5 binds selectively to the 5-HT2A receptor in the pig brain. Conclusion: 11C-CIMBI-5 showed a cortex-to-cerebellum binding ratio equal to the widely used 5-HT 2A antagonist PET tracer 18F-altanserin, indicating that 11C-CIMBI-5 has a sufficient target-to-background ratio for future clinical use and is displaceable by ketanserin in both rats and pigs. Thus, 11C-CIMBI-5 is a promising tool for investigation of 5-HT 2A agonist binding in the living human brain.

KW - Faculty of Health and Medical Sciences

U2 - 10.2967/jnumed.109.074021

DO - 10.2967/jnumed.109.074021

M3 - Journal article

C2 - 20956470

SN - 0161-5505

VL - 51

SP - 1763

EP - 1770

JO - The Journal of Nuclear Medicine

JF - The Journal of Nuclear Medicine

IS - 11

ER -