Fluorine-18 and carbon-11 labeled amphetamine analogs--synthesis, distribution, binding characteristics in mice and rats and a PET study in monkey.
No-carrier-added (NCA) (+-)-p-[18F]fluoroamphetamine (2a) and (+-)-6-[18F]fluoro-3,4-methylene-dioxy-amphetamine (2b) were synthesized through a multistep synthesis by nucleophilic substitution of the appropriate precursors (p-nitrobenzaldehyde, 1a and 6-nitropiperonal 1b, respectively) with [18F]fluoride followed by condensation with nitroethane and reduction with LAH in 20-30% yield (EOB) in a synthesis time of 90-109 min from EOB. NCA (-)-[11C]methamphetamine (4a) and (+-)-3,4-methylene-dioxy-N-[11C]methamphetamine (4b) were synthesized by methylation of the appropriate desmethyl precursors 3a and 3b with [11C]H3I in 40-60% yield (EOB) in a synthesis time of 30 min from EOB. Animal studies in mouse and rat revealed that the relative tissue uptake of these radiotracers was kidneys > lungs > liver > spleen > brain > heart > blood. The uptakes of these radiotracers in mouse brain were high and similar at 5 min post-injection (approx. 5%/g) but radioactivity then declined rapidly (approx. 1%/g at 60 min post-injection). For compounds 2a and 2b, the activity in the femur did not increase with time indicating in vivo defluorination may not be the major route of metabolism. Monoamine uptake inhibitors (nomifensine, fluoxetine and nisoxetine) did not inhibit but enhance the uptake of (-)-[11C]methamphetamine (4a) in the rat brain by greater than 50%. A PET study in a Rhesus monkey revealed that the uptakes of (-)-[11C]methamphetamine in different brain regions were similar and the retention of the radioactivity in these regions remained constant throughout the study. Analysis of arterial plasma by HPLC showed that 50% of radioactivity remained as 4a at 60 min post-injection.
Shiue
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Center for Metabolic Imaging, Creighton University, Omaha, NE 68108.
Shiue
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GG
Rysavy
J A
JA
Pleus
R C
RC
Huang
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Bai
L Q
LQ
Cornish
K G
KG
Sunderland
J J
JJ
Frick
M P
MP
D000662:Amphetamines / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000737:chemistry; D005260:Female; D005462:Fluorine Radioisotopes / Q000737:chemistry; D007553:Isotope Labeling / Q000379:methods; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D000662:Amphetamines; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes