Proof of mechanism study of a novel serotonin transporter blocker, DA-8031, using [11C]DASB positron emission tomography and in vivo microdialysis.
OBJECTIVE
To investigate the efficacy of DA-8031, a novel compound for the treatment of premature ejaculation, we measured serotonin transporter (SERT) occupancy by DA-8031, as well as DA-8031-induced changes in extracellular serotonin levels, in the rat brain using positron emission tomography (PET) and 11C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine ([11C]DASB) and in vivo microdialysis, respectively.


METHODS
[11C]DASB PET scans were performed in rats with graded doses of DA-8031 (vehicle: 10, 30, and 100 mg/kg). SERT occupancy in the midbrain was determined using binding potentials for [11C]DASB calculated by the multilinear reference tissue model. Extracellular serotonin levels were monitored in the dorsal raphe nucleus of rats after the administration of DA-8031 (10-100 mg/kg) using in vivo microdialysis.


RESULTS
PET data indicated a reduction of [11C]DASB binding to SERTs in the midbrain as a function of DA-8031 dose. SERT occupancy for each DA-8031 dose (10-100 mg/kg) ranged between 31% and 84%. The drug dose required for 50% occupancy of SERT was 13.5 mg/kg in the midbrain, comparable with previous preclinical behavioral data (∼10-30 mg/kg). In vivo microdialysis showed that DA-8031 produced a dose-dependent increase in extracellular serotonin levels in the dorsal raphe nucleus (33%-81% increase for doses of 10-100 mg/kg).


CONCLUSIONS
These preclinical data provide a proof of mechanism for DA-8031 as a novel compound of targeting the SERT for the treatment of premature ejaculation, warranting further clinical trials. They also offer insight into the optimal drug dose needed to exert therapeutic effects while minimizing adverse effects in humans.
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea; Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea; Advanced Institutes of Convergence Technology, Suwon, South Korea.
Hyun Soo
HS
Park
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.
In Soon
IS
Jung
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.
Nam Hee
NH
Lim
Dong-A Pharmaceutical Company, Yongin, South Korea.
Ji Hyun
JH
Sung
Department of Clinical Pharmacy, College of Pharmacy, Ajou University, Suwon, South Korea.
Sukhyang
S
Lee
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea.
Byung Seok
BS
Moon
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea; Advanced Institutes of Convergence Technology, Suwon, South Korea.
Byung Chul
BC
Lee
Dong-A Pharmaceutical Company, Yongin, South Korea.
Kyung Koo
KK
Kang
Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea; Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea; Advanced Institutes of Convergence Technology, Suwon, South Korea. Electronic address: kse@snu.ac.kr.
Sang Eun
SE
Kim
D000814:Aniline Compounds; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D004542:Ejaculation / Q000187:drug effects*; D008297:Male; D017551:Microdialysis; D049268:Positron-Emission Tomography; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects*; D013440:Sulfides; D013997:Time Factors
C412822:3-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile; D000814:Aniline Compounds; D001572:Benzofurans; D002250:Carbon Radioisotopes; C559089:DA 8031; D050486:Serotonin Plasma Membrane Transport Proteins; D013440:Sulfides