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

Anders Ettrup; Mikael Palner; Nicolas Gillings; Martin A Santini; Martin Hansen; Birgitte R Kornum; Lars Kildehøj Rasmussen; Kjell Åke Någren; Jacob Madsen; Mikael Begtrup; Gitte M Knudsen

doi:10.2967/jnumed.109.074021

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

Anders Ettrup, Mikael Palner, Nicolas Gillings, Martin A Santini, Martin Hansen, Birgitte R Kornum, Lars Kildehøj Rasmussen, Kjell Åke Någren, Jacob Madsen, Mikael Begtrup, Gitte M Knudsen

34 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Journal of Nuclear Medicine
Vol/bind	51
Udgave nummer	11
Sider (fra-til)	1763-70
Antal sider	8
ISSN	0161-5505
DOI	https://doi.org/10.2967/jnumed.109.074021
Status	Udgivet - 1 nov. 2010

Adgang til dokumentet

10.2967/jnumed.109.074021

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

Citationsformater

@article{7eeb18b57c9045fab3b8c80638fe2a1b,

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.",

author = "Anders Ettrup and Mikael Palner and Nicolas Gillings and Santini, {Martin A} and Martin Hansen and Kornum, {Birgitte R} and Rasmussen, {Lars Kildeh{\o}j} and N{\aa}gren, {Kjell {\AA}ke} and Jacob Madsen and Mikael Begtrup and Knudsen, {Gitte M}",

year = "2010",

month = nov,

day = "1",

doi = "10.2967/jnumed.109.074021",

language = "English",

volume = "51",

pages = "1763--70",

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, Nicolas

AU - Santini, Martin A

AU - Hansen, Martin

AU - Kornum, Birgitte R

AU - Rasmussen, Lars Kildehøj

AU - Någren, Kjell Åke

AU - Madsen, Jacob

AU - Begtrup, Mikael

AU - Knudsen, Gitte M

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.

U2 - 10.2967/jnumed.109.074021

DO - 10.2967/jnumed.109.074021

M3 - Journal article

SN - 0161-5505

VL - 51

SP - 1763

EP - 1770

JO - The Journal of Nuclear Medicine

JF - The Journal of Nuclear Medicine

IS - 11

ER -

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

Abstract

Adgang til dokumentet

Fingeraftryk

Citationsformater