Synthesis and Evaluation of Three 18F-Labeled Aminophenylbenzothiazoles as Amyloid Imaging Agents

Abstract

We have developed three fluorine-18 labeled 6-(methyl)amino-2-(4'-fluorophenyl)-1,3-benzothiazoles, which display high in vitro binding affinity for human amyloid beta plaques (K(i) < or = 10 nM). The radiolabeled probes were synthesized by aromatic nucleophilic substitution of the corresponding nitro precursor with (18)F-fluoride, followed by deprotection of the BOC group if required. Determination of the octanol/water partition coefficient, biodistribution studies in mice, and in vivo muPET studies in rats and a rhesus monkey showed that initial brain uptake was high and brain washout was fast in normal animals. Radiometabolites were quantified in plasma and brain of mice and in monkey plasma using HPLC. Of the tested compounds, [(18)F]2 (6-amino-2-(4'-[(18)F]fluorophenyl)-1,3-benzothiazole) shows the most favorable brain kinetics in mice, rats, and a monkey. Its polar plasma radiometabolites do not cross the blood-brain barrier. The preliminary results strongly suggest that this new fluorinated compound is a promising candidate as a PET brain amyloid imaging agent.