[Quick and simple synthesis of (11)C-(+)-alpha-dihydrotetrabenazine to be used as a PET radioligand of vesicular monoamine transporters].
Dihydrotetrabenazine (2-hydroxy-3-isobutyl-9,10-dimethoxy-1,3,4,6,7-hexahydro-11bH-benzo[a]-quinolizine, DTBZ) has become the ideal radioligand for the presynaptic vesicular monoamine transporter VMAT2 based on its high binding affinity and optimal lipophilicity.


OBJECTIVE
To develop an automatic procedure for labelling DTBZ with carbon-11, which has been shown to be a highly effective marker for in vivo studies of neuronal losses in animal models with Parkinson's disease using positron emission tomography (PET).


METHODS
We have developed a new fully automated synthesis procedure to obtain 11C-(+)DTBZ quickly and simply through labelling the precursor -(+)desmethyldihy-drotetrabenazine- at room temperature in the presence of dimethyl sulfoxide (DMSO) and potassium hydroxide (KOH), using 11CH3I as primary precursor. The final purification was carried out by solid phase extraction using commercially available cartridges and the residual solvents (DMSO and ethyl ether) were eliminated by evaporation.


RESULTS
The whole procedure was automated, and after 54 syntheses, an average production of 1.94 GBq of sterile, pyrogen-free 11C-(+)DTBZ with a radiochemical purity > 99 % was obtained with 5 minutes irradiation and 6 minutes of synthesis after 11CH3I production. 11C-(+)DTBZ binding to presynaptic dopamine nerve terminals has been demonstrated by MicroPET studies in Wistar rats and M. Fascicularis monkeys.


CONCLUSIONS
This new synthesis procedure is quick and simple, due to optimised techniques, which have allowed elimination of residual solvents based on their polarity for the final purification. It is also applicable to other automatic syntheses for obtaining compounds labelled by methylation reactions.
Quincoces
G
G
Unidad de Radiofarmacia, Servicio de Medicina Nuclear, Clínica Universitaria de Navarra, Pamplona, Navarra, Spain. gquinfer@unav.es
Collantes
M
M
Catalán
R
R
Ecay
M
M
Prieto
E
E
Martino
E
E
Blesa
F J
FJ
Alvarez-Erviti
L
L
Areses
P
P
Arbizu
J
J
Obeso
J A
JA
Martí-Climent
J M
JM
Richter
J A
JA
Peñuelas
I
I
D001331:Automation; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D004121:Dimethyl Sulfoxide; D004298:Dopamine; D004340:Drug Contamination; D004731:Endotoxins / Q000032:analysis; D004986:Ether; D006801:Humans; D007553:Isotope Labeling / Q000379:methods; D049268:Positron-Emission Tomography / Q000379:methods*; D017729:Presynaptic Terminals / Q000737:chemistry / Q000000981:diagnostic imaging* / Q000648:ultrastructure; D011786:Quality Control; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D017661:Receptors, Presynaptic / Q000737:chemistry; D012997:Solvents; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D050493:Vesicular Monoamine Transport Proteins / Q000032:analysis*
D002250:Carbon Radioisotopes; D004731:Endotoxins; D019275:Radiopharmaceuticals; D017661:Receptors, Presynaptic; C493449:SLC18A1 protein, human; C493452:SLC18A2 protein, human; D012997:Solvents; D050493:Vesicular Monoamine Transport Proteins; D004986:Ether; C032811:dihydrotetrabenazine; D004298:Dopamine; D004121:Dimethyl Sulfoxide; D013747:Tetrabenazine