TY - JOUR
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
Y1 - 2019/9/18
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 -