An improved radiosynthesis of [18F]AV-133: a PET imaging agent for vesicular monoamine transporter 2.
BACKGROUND
Recently, a PET tracer, 9-[(18)F]fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]AV-133), targeting vesicular monoamine transporter 2 (VMAT2) in the central nervous system has been reported. It is currently under Phase II clinical trials to establish its usefulness in the diagnosis of neurodegenerative diseases including dementia with Lewy bodies and Parkinson's disease. The radiolabeling of [(18)F]AV-133, nucleophilic fluorination reaction and potential effects of pseudo-carrier were evaluated by in vivo biodistribution.


METHODS
The preparation of [(18)F]AV-133 was evaluated under different conditions, specifically by employing different precursors (-OTs or -Br as the leaving group at the 9-propoxy position), reagents (K222/K(2)CO(3) vs. tributylammonium bicarbonate) and solvents (acetonitrile vs. DMSO), reaction temperature and reaction time. With optimized conditions from these experiments, radiosynthesis and purification with solid-phase extraction (SPE) of [(18)F]AV-133 were performed by an automated nucleophilic [(18)F]fluorination module. In vivo biodistribution in mice on [(18)F]AV-133 purified by either HPLC (no-carrier-added) or the SPE method (containing a pseudo-carrier) was performed and the results compared.


RESULTS
Under a mild fluorination condition (heating at 115 degrees C for 5 min in dimethyl sulfoxide), [(18)F]AV-133 was obtained in a high yield using either -OTs or -Br as the leaving group. However, the -OTs precursor gave better radiochemical yields (>70%, thin layer chromatography analysis) compared to those of the -Br precursor. The optimized reaction conditions were successfully implemented to an automated nucleophilic fluorination module. Labeling and purification of [(18)F]AV133 were readily achieved via this automatic module in good radiochemical yield of 21-41% (n=10) in 40 min. The radiochemical purity was larger than 95%. Biodistribution of SPE-purified product (containing a pseudo-carrier) in mice showed a high striatum/cerebellum ratio (4.18+/-0.51), which was comparable to that of HPLC-purified [(18)F]AV-133 (4.51+/-0.10).


CONCLUSIONS
The formation of [(18)F]AV-133 was evaluated under different labeling conditions. These improved labeling conditions and SPE purification were successfully implemented into an automated synthesis module. This offers a short preparation time (about 40 min), simplicity in operation and ready applicability for routine clinical operation.
Zhu
Lin
L
Key Laboratory of Radiopharmaceuticals, Beijing Normal University, Ministry of Education, Beijing 100875, PR China.
Liu
Yajing
Y
Plössl
Karl
K
Lieberman
Brian
B
Liu
Jingying
J
Kung
Hank F
HF
D000818:Animals; D001692:Biological Transport; D005462:Fluorine Radioisotopes; D054879:Halogenation; D008297:Male; D051379:Mice; D017072:Neostriatum / Q000378:metabolism; D010300:Parkinson Disease / Q000000981:diagnostic imaging / Q000378:metabolism; D049268:Positron-Emission Tomography; D052616:Solid Phase Extraction; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D014018:Tissue Distribution; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
D005462:Fluorine Radioisotopes; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; C549477:florbenazine F 18; D013747:Tetrabenazine