[18F]FE@SUPPY and [18F]FE@SUPPY:2--metabolic considerations.
BACKGROUND
Recently, [(18)F]FE@SUPPY and [(18)F]FE@SUPPY:2 were introduced as the first positron emission tomography (PET) tracers for the adenosine A(3) receptor. Thus, aim of the present study was the metabolic characterization of the two adenosine A(3) receptor PET tracers.


METHODS
In vitro carboxylesterase (CES) experiments were conducted using incubation mixtures containing different concentrations of the two substrates, porcine CES and phosphate-buffered saline. Enzymatic reactions were stopped by adding acetonitrile/methanol (10:1) after various time points and analyzed by a high-performance liquid chromatography (HPLC) standard protocol. In vivo experiments were conducted in male wild-type rats; tracers were injected through a tail vein. Rats were sacrificed after various time points (n=3), and blood and brain samples were collected. Sample cleanup was performed by an HPLC standard protocol.


RESULTS
The rate of enzymatic hydrolysis by CES demonstrated Michaelis-Menten constants in a micromolar range (FE@SUPPY, 20.15 microM, and FE@SUPPY:2, 13.11 microM) and limiting velocities of 0.035 and 0.015 microM/min for FE@SUPPY and FE@SUPPY:2, respectively. Degree of metabolism in blood showed the following: 15 min pi 47.7% of [(18)F]FE@SUPPY was intact compared to 33.1% of [(18)F]FE@SUPPY:2; 30 min pi 30.3% intact [(18)F]FE@SUPPY was found compared to 15.6% [(18)F]FE@SUPPY:2. In brain, [(18)F]FE@SUPPY:2 formed an early hydrophilic metabolite, whereas metabolism of [(18)F]FE@SUPPY was not observed before 30 min pi


CONCLUSIONS
Knowing that metabolism in rats is several times faster than in human, we conclude that [(18)F]FE@SUPPY should be stable for the typical time span of a clinical investigation. As a consequence, from a metabolic point of view, one would tend to decide in favor of [(18)F]FE@SUPPY.
Haeusler
Daniela
D
Department of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna, Austria.
Nics
Lukas
L
Mien
Leonhard-Key
LK
Ungersboeck
Johanna
J
Lanzenberger
Rupert R
RR
Shanab
Karem
K
Spreitzerf
Helmut
H
Sindelar
Karoline M
KM
Viernstein
Helmut
H
Wagner
Karl-Heinz
KH
Dudczak
Robert
R
Kletter
Kurt
K
Wadsak
Wolfgang
W
Mitterhauser
Markus
M
D000818:Animals; D043182:Carboxylesterase / Q000378:metabolism; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D008297:Male; D009539:Nicotinic Acids / Q000737:chemistry / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D011854:Radiochemistry; D051381:Rats
C528136:5-(2-fluoroethyl) 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate; D005462:Fluorine Radioisotopes; D009539:Nicotinic Acids; D011849:Radioactive Tracers; D043182:Carboxylesterase