Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers

Anders Ettrup; Martin Hansen; Martin A Santini; James Paine; Nic Gillings; Mikael Palner; Szabolcs Lehel; Matthias M Herth; Jacob Madsen; Jesper Kristensen; Mikael Begtrup; Gitte M Knudsen

doi:10.1007/s00259-010-1686-8

Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers

Anders Ettrup, Martin Hansen, Martin A Santini, James Paine, Nic Gillings, Mikael Palner, Szabolcs Lehel, Matthias M Herth, Jacob Madsen, Jesper Kristensen, Mikael Begtrup, Gitte M Knudsen

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

PURPOSE: Positron emission tomography (PET) imaging of serotonin 2A (5-HT(2A)) receptors with agonist tracers holds promise for the selective labelling of 5-HT(2A) receptors in their high-affinity state. We have previously validated [(11)C]Cimbi-5 and found that it is a 5-HT(2A) receptor agonist PET tracer. In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [(11)C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT(2A) receptor agonist PET tracers in the pig brain.

METHODS: Each radiotracer was injected intravenously into anaesthetized Danish Landrace pigs, and the pigs were subsequently scanned for 90 min in a high-resolution research tomography scanner. To evaluate 5-HT(2A) receptor binding, cortical nondisplaceable binding potentials (BP(ND)) were calculated using the simplified reference tissue model with the cerebellum as a reference region.

RESULTS: After intravenous injection, all compounds entered the brain and distributed preferentially into the cortical areas, in accordance with the known 5-HT(2A) receptor distribution. The largest target-to-background binding ratio was found for [(11)C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [(11)C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT(2A) receptor selectivity in vivo. [(11)C]Cimbi-82 and [(11)C]Cimbi-21 showed lower cortical BP(ND), while [(11)C]Cimbi-27, [(11)C]Cimbi-29, [(11)C]Cimbi-31 and [(11)C]Cimbi-88 gave rise to cortical BP(ND) similar to that of [(11)C]Cimbi-5.

CONCLUSION: [(11)C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT(2A) receptor agonist binding in the living human brain with PET.

Original language	English
Journal	European Journal of Nuclear Medicine and Molecular Imaging
Volume	38
Issue number	4
Pages (from-to)	681-693
ISSN	1619-7070
DOIs	https://doi.org/10.1007/s00259-010-1686-8
Publication status	Published - Apr 2011
Externally published	Yes

Keywords

Animals
Benzylamines/chemical synthesis
Biological Transport
Brain/metabolism
Carbon Radioisotopes
Female
Humans
Hydrolysis/drug effects
Injections, Intravenous
Ketanserin/pharmacology
Phenethylamines/chemical synthesis
Phosphatidylinositols/metabolism
Positron-Emission Tomography/methods
Radioactive Tracers
Radiochemistry
Receptor, Serotonin, 5-HT2A/metabolism
Serotonin 5-HT2 Receptor Agonists/chemical synthesis
Swine

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Ettrup, A., Hansen, M., Santini, M. A., Paine, J., Gillings, N., Palner, M., Lehel, S., Herth, M. M., Madsen, J., Kristensen, J., Begtrup, M., & Knudsen, G. M. (2011). Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers. European Journal of Nuclear Medicine and Molecular Imaging, 38(4), 681-693. https://doi.org/10.1007/s00259-010-1686-8

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title = "Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers",

abstract = "PURPOSE: Positron emission tomography (PET) imaging of serotonin 2A (5-HT(2A)) receptors with agonist tracers holds promise for the selective labelling of 5-HT(2A) receptors in their high-affinity state. We have previously validated [(11)C]Cimbi-5 and found that it is a 5-HT(2A) receptor agonist PET tracer. In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [(11)C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT(2A) receptor agonist PET tracers in the pig brain.METHODS: Each radiotracer was injected intravenously into anaesthetized Danish Landrace pigs, and the pigs were subsequently scanned for 90 min in a high-resolution research tomography scanner. To evaluate 5-HT(2A) receptor binding, cortical nondisplaceable binding potentials (BP(ND)) were calculated using the simplified reference tissue model with the cerebellum as a reference region.RESULTS: After intravenous injection, all compounds entered the brain and distributed preferentially into the cortical areas, in accordance with the known 5-HT(2A) receptor distribution. The largest target-to-background binding ratio was found for [(11)C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [(11)C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT(2A) receptor selectivity in vivo. [(11)C]Cimbi-82 and [(11)C]Cimbi-21 showed lower cortical BP(ND), while [(11)C]Cimbi-27, [(11)C]Cimbi-29, [(11)C]Cimbi-31 and [(11)C]Cimbi-88 gave rise to cortical BP(ND) similar to that of [(11)C]Cimbi-5.CONCLUSION: [(11)C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT(2A) receptor agonist binding in the living human brain with PET.",

keywords = "Animals, Benzylamines/chemical synthesis, Biological Transport, Brain/metabolism, Carbon Radioisotopes, Female, Humans, Hydrolysis/drug effects, Injections, Intravenous, Ketanserin/pharmacology, Phenethylamines/chemical synthesis, Phosphatidylinositols/metabolism, Positron-Emission Tomography/methods, Radioactive Tracers, Radiochemistry, Receptor, Serotonin, 5-HT2A/metabolism, Serotonin 5-HT2 Receptor Agonists/chemical synthesis, Swine",

author = "Anders Ettrup and Martin Hansen and Santini, {Martin A} and James Paine and Nic Gillings and Mikael Palner and Szabolcs Lehel and Herth, {Matthias M} and Jacob Madsen and Jesper Kristensen and Mikael Begtrup and Knudsen, {Gitte M}",

year = "2011",

month = apr,

doi = "10.1007/s00259-010-1686-8",

language = "English",

volume = "38",

pages = "681--693",

journal = "European Journal of Nuclear Medicine and Molecular Imaging",

issn = "1619-7070",

publisher = "Springer",

number = "4",

}

Ettrup, A, Hansen, M, Santini, MA, Paine, J, Gillings, N, Palner, M, Lehel, S, Herth, MM, Madsen, J, Kristensen, J, Begtrup, M & Knudsen, GM 2011, 'Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers', European Journal of Nuclear Medicine and Molecular Imaging, vol. 38, no. 4, pp. 681-693. https://doi.org/10.1007/s00259-010-1686-8

TY - JOUR

T1 - Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers

AU - Ettrup, Anders

AU - Hansen, Martin

AU - Santini, Martin A

AU - Paine, James

AU - Gillings, Nic

AU - Palner, Mikael

AU - Lehel, Szabolcs

AU - Herth, Matthias M

AU - Madsen, Jacob

AU - Kristensen, Jesper

AU - Begtrup, Mikael

AU - Knudsen, Gitte M

PY - 2011/4

Y1 - 2011/4

N2 - PURPOSE: Positron emission tomography (PET) imaging of serotonin 2A (5-HT(2A)) receptors with agonist tracers holds promise for the selective labelling of 5-HT(2A) receptors in their high-affinity state. We have previously validated [(11)C]Cimbi-5 and found that it is a 5-HT(2A) receptor agonist PET tracer. In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [(11)C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT(2A) receptor agonist PET tracers in the pig brain.METHODS: Each radiotracer was injected intravenously into anaesthetized Danish Landrace pigs, and the pigs were subsequently scanned for 90 min in a high-resolution research tomography scanner. To evaluate 5-HT(2A) receptor binding, cortical nondisplaceable binding potentials (BP(ND)) were calculated using the simplified reference tissue model with the cerebellum as a reference region.RESULTS: After intravenous injection, all compounds entered the brain and distributed preferentially into the cortical areas, in accordance with the known 5-HT(2A) receptor distribution. The largest target-to-background binding ratio was found for [(11)C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [(11)C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT(2A) receptor selectivity in vivo. [(11)C]Cimbi-82 and [(11)C]Cimbi-21 showed lower cortical BP(ND), while [(11)C]Cimbi-27, [(11)C]Cimbi-29, [(11)C]Cimbi-31 and [(11)C]Cimbi-88 gave rise to cortical BP(ND) similar to that of [(11)C]Cimbi-5.CONCLUSION: [(11)C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT(2A) receptor agonist binding in the living human brain with PET.

AB - PURPOSE: Positron emission tomography (PET) imaging of serotonin 2A (5-HT(2A)) receptors with agonist tracers holds promise for the selective labelling of 5-HT(2A) receptors in their high-affinity state. We have previously validated [(11)C]Cimbi-5 and found that it is a 5-HT(2A) receptor agonist PET tracer. In an attempt to further optimize the target-to-background binding ratio, we modified the chemical structure of the phenethylamine backbone and carbon-11 labelling site of [(11)C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT(2A) receptor agonist PET tracers in the pig brain.METHODS: Each radiotracer was injected intravenously into anaesthetized Danish Landrace pigs, and the pigs were subsequently scanned for 90 min in a high-resolution research tomography scanner. To evaluate 5-HT(2A) receptor binding, cortical nondisplaceable binding potentials (BP(ND)) were calculated using the simplified reference tissue model with the cerebellum as a reference region.RESULTS: After intravenous injection, all compounds entered the brain and distributed preferentially into the cortical areas, in accordance with the known 5-HT(2A) receptor distribution. The largest target-to-background binding ratio was found for [(11)C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [(11)C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT(2A) receptor selectivity in vivo. [(11)C]Cimbi-82 and [(11)C]Cimbi-21 showed lower cortical BP(ND), while [(11)C]Cimbi-27, [(11)C]Cimbi-29, [(11)C]Cimbi-31 and [(11)C]Cimbi-88 gave rise to cortical BP(ND) similar to that of [(11)C]Cimbi-5.CONCLUSION: [(11)C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT(2A) receptor agonist binding in the living human brain with PET.

KW - Animals

KW - Benzylamines/chemical synthesis

KW - Biological Transport

KW - Brain/metabolism

KW - Carbon Radioisotopes

KW - Female

KW - Humans

KW - Hydrolysis/drug effects

KW - Injections, Intravenous

KW - Ketanserin/pharmacology

KW - Phenethylamines/chemical synthesis

KW - Phosphatidylinositols/metabolism

KW - Positron-Emission Tomography/methods

KW - Radioactive Tracers

KW - Radiochemistry

KW - Receptor, Serotonin, 5-HT2A/metabolism

KW - Serotonin 5-HT2 Receptor Agonists/chemical synthesis

KW - Swine

U2 - 10.1007/s00259-010-1686-8

DO - 10.1007/s00259-010-1686-8

M3 - Journal article

C2 - 21174090

SN - 1619-7070

VL - 38

SP - 681

EP - 693

JO - European Journal of Nuclear Medicine and Molecular Imaging

JF - European Journal of Nuclear Medicine and Molecular Imaging

IS - 4

ER -

Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT (2A) agonist PET tracers

Abstract

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