Synthesis of high-specific-radioactivity 4- and 6-[F-18]fluorometaraminol-PET tracers for the adrenergic nervous system of the heart

Fluorine-18- (t(1/2) 109.8 min) and carbon-11 (t(1/2) 20.4 min)-labeled nor epinephrine analogues have been round previously to be useful positron-emis sion-tomography (PET) radioligands to map adrenergic nerve terminals of the heart. Metaraminol ((1R,2S)-2-amino-1-(3-hydroxyphenyl)-1-propanol) is a m etabolically stable structural analogue of norepinephrine and possesses hig h affinity towards the norepinephrine transporter and the vesicular monoami ne transporter. This paper presents the radiosynthesis of new positron-emis sion-tomography halogeno analogues of metaraminol labeled with high specifi c radioactivity. Firstly, fluorine-18-labeled 4-fluorometaraminol (4-[F-18] FMR or (1R,2S)-2-amino-1-(4-[F-18]fluoro-3-hydroxyphenyl)-1-propanol) and i ts three other stereoisomers were prepared based on the following key steps : (a) condensation of the corresponding no-carrier-added labeled fluorobenz aldehyde with nitroethane, and (b) HPLC (C18 and chiral) resolution of the diastereomeric product mixture into the four individual enantiomers. Second ly, the corresponding B-fluoro analogues, fluorine-18-labeled 6-fluorometar aminol (6-[F-18]FMR or (1R,2S)-2-amino-1-(2-[F-18]fluoro-5 hydroxyphenyl)-1 -propanol) and its three other enantiomers, were prepared in an analogous w ay. Typically, 0.48-0.55 GBq of 4-[F-18]FMR and 0.14-0.15 GBq of 6-[F-18]FM R could he obtained after 120-160 min total synthesis time, with a specific radioactivity of 56-106 GBq/mu mol. Furthermore, the synthesis of racemic 4-fluorometaraminol and 6-fluorometaraminol as reference compounds was perf ormed, as well as independent chiral syntheses of the optically active (1R, 2S) enantiomers. For the chiral synthesis, the key step was an electrophili c fluorination with acetyl hypofluorite of (1R,2S)configurated organometall ic derivatives of metaraminol. Tissue distribution studies in rats suggeste d that both 4-[F-18]FMR and 6-[F-18]FMR display similar affinity towards th e presynaptic adrenergic nerve terminal in the heart. From a practical poin t of view, 4-[F-18]FMR appeared to be the more attractive candidate for fut ure PET investigations, due to higher radiochemical yields. (C) 2001 Elsevi er Science Ltd. All rights reserved.