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^*

^*Corresponding author for this work

Department of Clinical Medicine

3 Citations (Scopus)

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
Number of pages	8
ISSN	1948-7193
DOIs	https://doi.org/10.1021/acschemneuro.9b00132
Publication status	Published - 18 Sept 2019

Keywords

5-HT R
fluorine-18
fragment-based dual-labeling
PDSP
PET
rat

Access to Document

10.1021/acschemneuro.9b00132

Cite this

@article{c0846930aff945cfb2ab86e56f69b264,

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.",

keywords = "5-HT R, fluorine-18, fragment-based dual-labeling, PDSP, PET, rat",

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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T1 - Development and Evaluation of Two Potential 5-HT7 Receptor PET Tracers

T2 - [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 - 5-HT R

KW - fluorine-18

KW - fragment-based dual-labeling

KW - PDSP

KW - PET

KW - rat

U2 - 10.1021/acschemneuro.9b00132

DO - 10.1021/acschemneuro.9b00132

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