Synthesis and evaluation of 18F-labeled 5-HT2A receptor agonists as PET ligands

Matthias M Herth; Ida Nymann Petersen; Hanne Demant Hansen; Martin Hansen; Anders Ettrup; Anders A Jensen; Szabolcs Lehel; Agnete Dyssegaard; Nic Gillings; Gitte M Knudsen; Jesper L Kristensen

doi:10.1016/j.nucmedbio.2016.02.011

Synthesis and evaluation of 18F-labeled 5-HT2A receptor agonists as PET ligands

Matthias M Herth, Ida Nymann Petersen, Hanne Demant Hansen, Martin Hansen, Anders Ettrup, Anders A Jensen, Szabolcs Lehel, Agnete Dyssegaard, Nic Gillings, Gitte M Knudsen, Jesper L Kristensen

15 Citations (Scopus)

Abstract

INTRODUCTION: The serotonin 2A receptor (5-HT2AR) is the most abundant excitatory 5-HT receptor in the human brain and implicated in various brain disorders such as schizophrenia, depression, and Alzheimer's disease. Positron emission tomography (PET) can be used to image specific proteins and processes in the human brain and several 5-HT2AR PET antagonist radioligands are available. In contrast to an antagonist radioligand, an agonist radioligand should be able to image the population of functional receptors, i.e., those capable of inducing neuroreceptor signaling. Recently, we successfully developed and validated the first 5-HT2AR agonist PET tracer, [(11)C]Cimbi-36, for neuroimaging in humans and herein disclose some of our efforts to develop an (18)F-labeled 5-HT2AR agonist PET-ligand.

METHODS AND RESULTS: Three fluorine containing derivatives of Cimbi-36 were synthesized and found to be potent 5-HT2A agonists. (18)F-labeling of the appropriate precursors was performed using [(18)F]FETos, typically yielding 0.2-2.0GBq and specific activities of 40-120GBq/μmol. PET studies in Danish landrace pigs revealed that [(18)F]1 displayed brain uptake in 5-HT2AR rich regions. However, high uptake in bone was also observed. No blocking effect was detected during a competition experiment with a 5-HT2AR selective antagonist. [(18)F]2 and [(18)F]3 showed very low brain uptake.

CONCLUSION: None of the investigated (18)F-labeled Cimbi-36 derivatives [(18)F]1, [(18)F]2 and [(18)F]3 show suitable tracer characteristics for in vivo PET neuroimaging of the 5-HT2AR. Although for [(18)F]1 there was reasonable brain uptake, we suggest that a large proportion radioactivity in the brain was due to radiometabolites, which would explain why it could not be displaced by a 5-HT2AR antagonist.

Original language	English
Journal	Nuclear Medicine and Biology
Volume	43
Issue number	8
Pages (from-to)	455-462
Number of pages	8
ISSN	0969-8051
DOIs	https://doi.org/10.1016/j.nucmedbio.2016.02.011
Publication status	Published - 1 Aug 2016

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10.1016/j.nucmedbio.2016.02.011

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title = "Synthesis and evaluation of 18F-labeled 5-HT2A receptor agonists as PET ligands",

abstract = "INTRODUCTION: The serotonin 2A receptor (5-HT2AR) is the most abundant excitatory 5-HT receptor in the human brain and implicated in various brain disorders such as schizophrenia, depression, and Alzheimer's disease. Positron emission tomography (PET) can be used to image specific proteins and processes in the human brain and several 5-HT2AR PET antagonist radioligands are available. In contrast to an antagonist radioligand, an agonist radioligand should be able to image the population of functional receptors, i.e., those capable of inducing neuroreceptor signaling. Recently, we successfully developed and validated the first 5-HT2AR agonist PET tracer, [(11)C]Cimbi-36, for neuroimaging in humans and herein disclose some of our efforts to develop an (18)F-labeled 5-HT2AR agonist PET-ligand.METHODS AND RESULTS: Three fluorine containing derivatives of Cimbi-36 were synthesized and found to be potent 5-HT2A agonists. (18)F-labeling of the appropriate precursors was performed using [(18)F]FETos, typically yielding 0.2-2.0GBq and specific activities of 40-120GBq/μmol. PET studies in Danish landrace pigs revealed that [(18)F]1 displayed brain uptake in 5-HT2AR rich regions. However, high uptake in bone was also observed. No blocking effect was detected during a competition experiment with a 5-HT2AR selective antagonist. [(18)F]2 and [(18)F]3 showed very low brain uptake.CONCLUSION: None of the investigated (18)F-labeled Cimbi-36 derivatives [(18)F]1, [(18)F]2 and [(18)F]3 show suitable tracer characteristics for in vivo PET neuroimaging of the 5-HT2AR. Although for [(18)F]1 there was reasonable brain uptake, we suggest that a large proportion radioactivity in the brain was due to radiometabolites, which would explain why it could not be displaced by a 5-HT2AR antagonist.",

author = "Herth, {Matthias M} and Petersen, {Ida Nymann} and Hansen, {Hanne Demant} and Martin Hansen and Anders Ettrup and Jensen, {Anders A} and Szabolcs Lehel and Agnete Dyssegaard and Nic Gillings and Knudsen, {Gitte M} and Kristensen, {Jesper L}",

year = "2016",

month = aug,

day = "1",

doi = "10.1016/j.nucmedbio.2016.02.011",

language = "English",

volume = "43",

pages = "455--462",

journal = "Nuclear Medicine and Biology",

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T1 - Synthesis and evaluation of 18F-labeled 5-HT2A receptor agonists as PET ligands

AU - Herth, Matthias M

AU - Petersen, Ida Nymann

AU - Hansen, Hanne Demant

AU - Hansen, Martin

AU - Ettrup, Anders

AU - Jensen, Anders A

AU - Lehel, Szabolcs

AU - Dyssegaard, Agnete

AU - Gillings, Nic

AU - Knudsen, Gitte M

AU - Kristensen, Jesper L

PY - 2016/8/1

Y1 - 2016/8/1

N2 - INTRODUCTION: The serotonin 2A receptor (5-HT2AR) is the most abundant excitatory 5-HT receptor in the human brain and implicated in various brain disorders such as schizophrenia, depression, and Alzheimer's disease. Positron emission tomography (PET) can be used to image specific proteins and processes in the human brain and several 5-HT2AR PET antagonist radioligands are available. In contrast to an antagonist radioligand, an agonist radioligand should be able to image the population of functional receptors, i.e., those capable of inducing neuroreceptor signaling. Recently, we successfully developed and validated the first 5-HT2AR agonist PET tracer, [(11)C]Cimbi-36, for neuroimaging in humans and herein disclose some of our efforts to develop an (18)F-labeled 5-HT2AR agonist PET-ligand.METHODS AND RESULTS: Three fluorine containing derivatives of Cimbi-36 were synthesized and found to be potent 5-HT2A agonists. (18)F-labeling of the appropriate precursors was performed using [(18)F]FETos, typically yielding 0.2-2.0GBq and specific activities of 40-120GBq/μmol. PET studies in Danish landrace pigs revealed that [(18)F]1 displayed brain uptake in 5-HT2AR rich regions. However, high uptake in bone was also observed. No blocking effect was detected during a competition experiment with a 5-HT2AR selective antagonist. [(18)F]2 and [(18)F]3 showed very low brain uptake.CONCLUSION: None of the investigated (18)F-labeled Cimbi-36 derivatives [(18)F]1, [(18)F]2 and [(18)F]3 show suitable tracer characteristics for in vivo PET neuroimaging of the 5-HT2AR. Although for [(18)F]1 there was reasonable brain uptake, we suggest that a large proportion radioactivity in the brain was due to radiometabolites, which would explain why it could not be displaced by a 5-HT2AR antagonist.

AB - INTRODUCTION: The serotonin 2A receptor (5-HT2AR) is the most abundant excitatory 5-HT receptor in the human brain and implicated in various brain disorders such as schizophrenia, depression, and Alzheimer's disease. Positron emission tomography (PET) can be used to image specific proteins and processes in the human brain and several 5-HT2AR PET antagonist radioligands are available. In contrast to an antagonist radioligand, an agonist radioligand should be able to image the population of functional receptors, i.e., those capable of inducing neuroreceptor signaling. Recently, we successfully developed and validated the first 5-HT2AR agonist PET tracer, [(11)C]Cimbi-36, for neuroimaging in humans and herein disclose some of our efforts to develop an (18)F-labeled 5-HT2AR agonist PET-ligand.METHODS AND RESULTS: Three fluorine containing derivatives of Cimbi-36 were synthesized and found to be potent 5-HT2A agonists. (18)F-labeling of the appropriate precursors was performed using [(18)F]FETos, typically yielding 0.2-2.0GBq and specific activities of 40-120GBq/μmol. PET studies in Danish landrace pigs revealed that [(18)F]1 displayed brain uptake in 5-HT2AR rich regions. However, high uptake in bone was also observed. No blocking effect was detected during a competition experiment with a 5-HT2AR selective antagonist. [(18)F]2 and [(18)F]3 showed very low brain uptake.CONCLUSION: None of the investigated (18)F-labeled Cimbi-36 derivatives [(18)F]1, [(18)F]2 and [(18)F]3 show suitable tracer characteristics for in vivo PET neuroimaging of the 5-HT2AR. Although for [(18)F]1 there was reasonable brain uptake, we suggest that a large proportion radioactivity in the brain was due to radiometabolites, which would explain why it could not be displaced by a 5-HT2AR antagonist.

U2 - 10.1016/j.nucmedbio.2016.02.011

DO - 10.1016/j.nucmedbio.2016.02.011

M3 - Journal article

C2 - 27209485

SN - 0969-8051

VL - 43

SP - 455

EP - 462

JO - Nuclear Medicine and Biology

JF - Nuclear Medicine and Biology

IS - 8

ER -

Synthesis and evaluation of 18F-labeled 5-HT2A receptor agonists as PET ligands

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