Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers

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

92 Citations (Scopus)

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 [¹¹C]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 [ ¹¹C]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 [¹¹C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [¹¹C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT_2A receptor selectivity in vivo. [¹¹C]Cimbi-82 and [¹¹C]Cimbi-21 showed lower cortical BP_ND, while [¹¹C]Cimbi-27, [¹¹C]Cimbi- 29, [¹¹C]Cimbi-31 and [¹¹C]Cimbi-88 gave rise to cortical BP_ND similar to that of [¹¹C]Cimbi-5. Conclusion: [ ¹¹C]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 - 1 Apr 2011

Keywords

Faculty of Health and Medical Sciences

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10.1007/s00259-010-1686-8

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Ettrup, A., Hansen, M., Santini, M. A., Paine, J. S., Gillings, N., Palner, M., Lehel, S., Herth, M. M., Madsen, J., Kristensen, J. L., 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

Ettrup, A, Hansen, M, Santini, MA, Paine, JS, Gillings, N, Palner, M, Lehel, S, Herth, MM, Madsen, J, Kristensen, JL, 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

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title = "Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers",

abstract = "Purpose: Positron emission tomography (PET) imaging of serotonin 2A (5-HT2A) receptors with agonist tracers holds promise for the selective labelling of 5-HT2A receptors in their high-affinity state. We have previously validated [11C]Cimbi-5 and found that it is a 5-HT2A 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 [ 11C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT2A 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 (BPND) 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-HT2A receptor distribution. The largest target-to-background binding ratio was found for [11C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [11C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT2A receptor selectivity in vivo. [11C]Cimbi-82 and [11C]Cimbi-21 showed lower cortical BPND, while [11C]Cimbi-27, [11C]Cimbi- 29, [11C]Cimbi-31 and [11C]Cimbi-88 gave rise to cortical BPND similar to that of [11C]Cimbi-5. Conclusion: [ 11C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT2A receptor agonist binding in the living human brain with PET.",

keywords = "Faculty of Health and Medical Sciences",

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

note = "Keywords: PET tracer development, 5-HT(2A), agonist, porcine, serotonin receptors, [11C]Cimbi-36",

year = "2011",

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

language = "English",

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pages = "681--693",

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

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T1 - Radiosynthesis and in vivo evaluation of a series of substituted 11C-phenethylamines as 5-HT2A agonist PET tracers

AU - Ettrup, Anders

AU - Hansen, Martin

AU - Santini, Martin A

AU - Paine, James Stephen

AU - Gillings, Nic

AU - Palner, Mikael

AU - Lehel, Szabolcs

AU - Herth, Matthias Manfred

AU - Madsen, Jacob

AU - Kristensen, Jesper Langgaard

AU - Begtrup, Mikael

AU - Knudsen, Gitte Moos

N1 - Keywords: PET tracer development, 5-HT(2A), agonist, porcine, serotonin receptors, [11C]Cimbi-36

PY - 2011/4/1

Y1 - 2011/4/1

N2 - Purpose: Positron emission tomography (PET) imaging of serotonin 2A (5-HT2A) receptors with agonist tracers holds promise for the selective labelling of 5-HT2A receptors in their high-affinity state. We have previously validated [11C]Cimbi-5 and found that it is a 5-HT2A 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 [ 11C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT2A 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 (BPND) 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-HT2A receptor distribution. The largest target-to-background binding ratio was found for [11C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [11C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT2A receptor selectivity in vivo. [11C]Cimbi-82 and [11C]Cimbi-21 showed lower cortical BPND, while [11C]Cimbi-27, [11C]Cimbi- 29, [11C]Cimbi-31 and [11C]Cimbi-88 gave rise to cortical BPND similar to that of [11C]Cimbi-5. Conclusion: [ 11C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT2A receptor agonist binding in the living human brain with PET.

AB - Purpose: Positron emission tomography (PET) imaging of serotonin 2A (5-HT2A) receptors with agonist tracers holds promise for the selective labelling of 5-HT2A receptors in their high-affinity state. We have previously validated [11C]Cimbi-5 and found that it is a 5-HT2A 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 [ 11C]Cimbi-5 in different ways. Here, we present the in vivo validation of nine novel 5-HT2A 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 (BPND) 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-HT2A receptor distribution. The largest target-to-background binding ratio was found for [11C]Cimbi-36 which also had a high brain uptake compared to its analogues. The cortical binding of [11C]Cimbi-36 was decreased by pretreatment with ketanserin, supporting 5-HT2A receptor selectivity in vivo. [11C]Cimbi-82 and [11C]Cimbi-21 showed lower cortical BPND, while [11C]Cimbi-27, [11C]Cimbi- 29, [11C]Cimbi-31 and [11C]Cimbi-88 gave rise to cortical BPND similar to that of [11C]Cimbi-5. Conclusion: [ 11C]Cimbi-36 is currently the most promising candidate for investigation of 5-HT2A receptor agonist binding in the living human brain with PET.

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U2 - 10.1007/s00259-010-1686-8

DO - 10.1007/s00259-010-1686-8

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JO - European Journal of Nuclear Medicine and Molecular Imaging

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