Development and Evaluation of Two Potential 5-HT7 Receptor PET Tracers: [18F]ENL09 and [18F]ENL10

Elina Tampio L'Estrade; Mengfei Xiong; Vladimir Shalgunov; Fraser G Edgar; Balázs Volk; Simone L Baerentzen; Mikael Palner; Maria Erlandsson; Tomas Ohlsson; Gitte M Knudsen; Matthias M Herth

doi:10.1021/acschemneuro.9b00132

Development and Evaluation of Two Potential 5-HT7 Receptor PET Tracers: [18F]ENL09 and [18F]ENL10

Elina Tampio L'Estrade, Mengfei Xiong, Vladimir Shalgunov, Fraser G Edgar, Balázs Volk, Simone L Baerentzen, Mikael Palner, Maria Erlandsson, Tomas Ohlsson, Gitte M Knudsen, Matthias M Herth

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

Abstract

The latest addition to the serotonin (5-HT) receptor family is the 5-HT7 receptor (5-HT7R). This receptor has gained interest as a drug target due to its involvement in various disorders such as depression or schizophrenia. There is currently no clinically validated positron emission tomography (PET) tracer for the 5-HT7R available. But, the (arylpiperazinyl-butyl)oxindole scaffold provides a promising lead structure for this purpose. Here, we synthesized 12 (arylpiperazinyl-butyl)oxindole derivatives and in vitro affinity screening identified two structures with suitable affinity and selectivity to be radiolabeled and tested as 5-HT7R selective PET tracers. Next, the radiolabeled products [18F]ENL09 and [18F]ENL10 were evaluated as PET tracers in rats. Both tracers were found to be P-gp substrates, but after P-gp inhibition the brain uptake showed a regional distribution in line with the known 5-HT7R distribution. The [18F]ENL10 brain binding was displaceable with a 5-HT7R selective ligand, whereas [18F]ENL09 was not. We find that [18F]ENL10 is a promising 5-HT7R selective PET tracer candidate that should be investigated in higher species.

Original language	English
Journal	ACS Chemical Neuroscience
Volume	10
Issue number	9
Pages (from-to)	3961-3968
ISSN	1948-7193
DOIs	https://doi.org/10.1021/acschemneuro.9b00132
Publication status	Published - 18. Sept 2019
Externally published	Yes

Keywords

Animals
Brain/diagnostic imaging
Drug Development/methods
Drug Evaluation, Preclinical/methods
Female
Fluorine Radioisotopes/administration & dosage
Injections, Intravenous
Positron-Emission Tomography/methods
Rats
Rats, Long-Evans
Receptors, Serotonin/metabolism
Serotonin Antagonists/administration & dosage

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10.1021/acschemneuro.9b00132

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title = "Development and Evaluation of Two Potential 5-HT7 Receptor PET Tracers: [18F]ENL09 and [18F]ENL10",

abstract = "The latest addition to the serotonin (5-HT) receptor family is the 5-HT7 receptor (5-HT7R). This receptor has gained interest as a drug target due to its involvement in various disorders such as depression or schizophrenia. There is currently no clinically validated positron emission tomography (PET) tracer for the 5-HT7R available. But, the (arylpiperazinyl-butyl)oxindole scaffold provides a promising lead structure for this purpose. Here, we synthesized 12 (arylpiperazinyl-butyl)oxindole derivatives and in vitro affinity screening identified two structures with suitable affinity and selectivity to be radiolabeled and tested as 5-HT7R selective PET tracers. Next, the radiolabeled products [18F]ENL09 and [18F]ENL10 were evaluated as PET tracers in rats. Both tracers were found to be P-gp substrates, but after P-gp inhibition the brain uptake showed a regional distribution in line with the known 5-HT7R distribution. The [18F]ENL10 brain binding was displaceable with a 5-HT7R selective ligand, whereas [18F]ENL09 was not. We find that [18F]ENL10 is a promising 5-HT7R selective PET tracer candidate that should be investigated in higher species.",

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author = "{Tampio L'Estrade}, Elina and Mengfei Xiong and Vladimir Shalgunov and Edgar, {Fraser G} and Bal{\'a}zs Volk and Baerentzen, {Simone L} and Mikael Palner and Maria Erlandsson and Tomas Ohlsson and Knudsen, {Gitte M} and Herth, {Matthias M}",

year = "2019",

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doi = "10.1021/acschemneuro.9b00132",

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T1 - Development and Evaluation of Two Potential 5-HT7 Receptor PET Tracers: [18F]ENL09 and [18F]ENL10

AU - Tampio L'Estrade, Elina

AU - Xiong, Mengfei

AU - Shalgunov, Vladimir

AU - Edgar, Fraser G

AU - Volk, Balázs

AU - Baerentzen, Simone L

AU - Palner, Mikael

AU - Erlandsson, Maria

AU - Ohlsson, Tomas

AU - Knudsen, Gitte M

AU - Herth, Matthias M

PY - 2019/9/18

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N2 - The latest addition to the serotonin (5-HT) receptor family is the 5-HT7 receptor (5-HT7R). This receptor has gained interest as a drug target due to its involvement in various disorders such as depression or schizophrenia. There is currently no clinically validated positron emission tomography (PET) tracer for the 5-HT7R available. But, the (arylpiperazinyl-butyl)oxindole scaffold provides a promising lead structure for this purpose. Here, we synthesized 12 (arylpiperazinyl-butyl)oxindole derivatives and in vitro affinity screening identified two structures with suitable affinity and selectivity to be radiolabeled and tested as 5-HT7R selective PET tracers. Next, the radiolabeled products [18F]ENL09 and [18F]ENL10 were evaluated as PET tracers in rats. Both tracers were found to be P-gp substrates, but after P-gp inhibition the brain uptake showed a regional distribution in line with the known 5-HT7R distribution. The [18F]ENL10 brain binding was displaceable with a 5-HT7R selective ligand, whereas [18F]ENL09 was not. We find that [18F]ENL10 is a promising 5-HT7R selective PET tracer candidate that should be investigated in higher species.

AB - The latest addition to the serotonin (5-HT) receptor family is the 5-HT7 receptor (5-HT7R). This receptor has gained interest as a drug target due to its involvement in various disorders such as depression or schizophrenia. There is currently no clinically validated positron emission tomography (PET) tracer for the 5-HT7R available. But, the (arylpiperazinyl-butyl)oxindole scaffold provides a promising lead structure for this purpose. Here, we synthesized 12 (arylpiperazinyl-butyl)oxindole derivatives and in vitro affinity screening identified two structures with suitable affinity and selectivity to be radiolabeled and tested as 5-HT7R selective PET tracers. Next, the radiolabeled products [18F]ENL09 and [18F]ENL10 were evaluated as PET tracers in rats. Both tracers were found to be P-gp substrates, but after P-gp inhibition the brain uptake showed a regional distribution in line with the known 5-HT7R distribution. The [18F]ENL10 brain binding was displaceable with a 5-HT7R selective ligand, whereas [18F]ENL09 was not. We find that [18F]ENL10 is a promising 5-HT7R selective PET tracer candidate that should be investigated in higher species.

KW - Animals

KW - Brain/diagnostic imaging

KW - Drug Development/methods

KW - Drug Evaluation, Preclinical/methods

KW - Female

KW - Fluorine Radioisotopes/administration & dosage

KW - Injections, Intravenous

KW - Positron-Emission Tomography/methods

KW - Rats

KW - Rats, Long-Evans

KW - Receptors, Serotonin/metabolism

KW - Serotonin Antagonists/administration & dosage

U2 - 10.1021/acschemneuro.9b00132

DO - 10.1021/acschemneuro.9b00132

M3 - Journal article

C2 - 30973705

SN - 1948-7193

VL - 10

SP - 3961

EP - 3968

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

IS - 9

ER -

Development and Evaluation of Two Potential 5-HT7 Receptor PET Tracers: [18F]ENL09 and [18F]ENL10

Abstract

Keywords

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