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

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 - 2019/9/18

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 - 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

SN - 1948-7193

VL - 10

SP - 3961

EP - 3968

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

IS - 9

ER -