Synthesis of high-specific-radioactivity 4- and 6-[18F]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 norepinephrine analogues have been found previously to be useful positron-emission-tomography (PET) radioligands to map adrenergic nerve terminals of the heart. Metaraminol ((1R,2S)-2-amino-1-(3-hydroxyphenyl)-1-propanol) is a metabolically stable structural analogue of norepinephrine and possesses high affinity towards the norepinephrine transporter and the vesicular monoamine transporter. This paper presents the radiosynthesis of new positron-emission-tomography halogeno analogues of metaraminol labeled with high specific radioactivity. Firstly, fluorine-18-labeled 4-fluorometaraminol (4-[18F]FMR or (1R,2S)-2-amino-1-(4-[18F]fluoro-3-hydroxyphenyl)-1-propanol) and its three other stereoisomers were prepared based on the following key steps: (a) condensation of the corresponding no-carrier-added labeled fluorobenzaldehyde with nitroethane, and (b) HPLC (C18 and chiral) resolution of the diastereomeric product mixture into the four individual enantiomers. Secondly, the corresponding 6-fluoro analogues, fluorine-18-labeled 6-fluorometaraminol (6-[18F]FMR or (1R,2S)-2-amino-1-(2-[18F]fluoro-5-hydroxyphenyl)-1-propanol) and its three other enantiomers, were prepared in an analogous way. Typically, 0.48-0.55 GBq of 4-[18F]FMR and 0.14-0.15 GBq of 6-[18F]FMR could be obtained after 120-160 min total synthesis time, with a specific radioactivity of 56-106 GBq/micromol. Furthermore, the synthesis of racemic 4-fluorometaraminol and 6-fluorometaraminol as reference compounds was performed. as well as independent chiral syntheses of the optically active (1R,2S) enantiomers. For the chiral syntheses, the key step was an electrophilic fluorination with acetyl hypofluorite of (1R,2S)-configurated organometallic derivatives of metaraminol. Tissue distribution studies in rats suggested that both 4-[18F]FMR and 6-[18F]FMR display similar affinity towards the presynaptic adrenergic nerve terminal in the heart. From a practical point of view, 4-[18F]FMR appeared to be the more attractive candidate for future PET investigations, due to higher radiochemical yields.
Langer
O
O
Service Hospitalier Frédéric Joliot, Département de Recherche Médicale, CEA, Orsay, France.
Dollé
F
F
Valette
H
H
Halldin
C
C
Vaufrey
F
F
Fuseau
C
C
Coulon
C
C
Ottaviani
M
M
Någren
K
K
Bottlaender
M
M
Maziére
B
B
Crouzel
C
C
D000818:Animals; D006321:Heart / Q000000981:diagnostic imaging* / Q000294:innervation* / Q000502:physiology; D008168:Lung; D008297:Male; D008680:Metaraminol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D009928:Organ Specificity; D011829:Radiation Dosage; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013564:Sympathetic Nervous System; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
C413488:4-fluorometaraminol; D019275:Radiopharmaceuticals; C054817:6-fluorometaraminol; D008680:Metaraminol