Development and Evaluation of Two Potential 5-HT7 Receptor PET Tracers: [18F]ENL09 and [18F]ENL10
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Development and Evaluation of Two Potential 5-HT7 Receptor PET Tracers : [18F]ENL09 and [18F]ENL10. / Tampio L'Estrade, Elina; Xiong, Mengfei; Shalgunov, Vladimir; Edgar, Fraser G.; Volk, Balázs; Baerentzen, Simone L.; Palner, Mikael; Erlandsson, Maria; Ohlsson, Tomas; Knudsen, Gitte M.; Herth, Matthias M.
In: ACS Chemical Neuroscience, Vol. 10, No. 9, 2019, p. 3961-3968.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
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
Y1 - 2019
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
M3 - Journal article
C2 - 30973705
AN - SCOPUS:85065136356
VL - 10
SP - 3961
EP - 3968
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 9
ER -
ID: 218307886