Measurement of brain concentration of FK960 for development of a novel antidementia drug: a PET study in conscious rhesus monkeys.
This study used PET to measure the time course of the brain concentration of (18)F-labeled N-(4-acetyl-1-piperazinyl)-p-fluorobenzamide monohydrate (FK960), a novel antidementia drug, after oral administration to conscious rhesus monkeys.


METHODS
Three young-adult male rhesus monkeys were tested. FK960 (0.1 mg/kg) containing about 370 MBq of (18)F-FK960 was administered orally to each monkey. Dynamic PET images were acquired for 4 h from 5 min after the administration. Arterial blood samples were withdrawn during PET scanning and were analyzed by an automatic well gamma-counter and thin-layer chromatography to determine the time course of authentic (18)F-FK960 activity concentration in plasma. FK960 concentrations in brain and plasma were calculated in units of mol/L using the specific activity of FK960 preparations.


RESULTS
(18)F-FK960 penetrated the blood-brain barrier and underwent perfusion-dependent distribution in the entire brain. Maximal concentrations in the brain and plasma were 1.11 +/- 0.30 x 10(-7) mol/L (at 3.0 +/- 0.6 h after administration) and 4.04 +/- 1.29 x 10(-7) mol/L (at 2.0 +/- 1.1 h after administration), respectively.


CONCLUSIONS
We succeeded in measuring the FK960 concentration in the brains of conscious monkeys and in plasma after oral administration at a dose of 0.1 mg/kg. The results suggested that this method can measure the FK960 concentration in the human brain, and a potential use of the PET technique in drug development was demonstrated.
Noda
Akihiro
A
The Medical and Pharmacological Research Center Foundation, Hakui, Japan. anoda@mprcf.or.jp
Takamatsu
Hiroyuki
H
Murakami
Yoshihiro
Y
Yajima
Kazuyoshi
K
Tatsumi
Mitsuyoshi
M
Ichise
Rikiya
R
Nishimura
Shintaro
S
D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D001921:Brain / Q000378:metabolism*; D003243:Consciousness; D003704:Dementia / Q000188:drug therapy; D005462:Fluorine Radioisotopes / Q000097:blood* / Q000493:pharmacokinetics*; D007553:Isotope Labeling / Q000379:methods; D008253:Macaca mulatta; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000097:blood / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D001549:Benzamides; D005462:Fluorine Radioisotopes; C102991:N-(4-acetyl-1-piperazinyl) -4-fluorobenzamide monohydrate; D010879:Piperazines; D019275:Radiopharmaceuticals