Synthesis of a [F]fluorobenzothiazole as potential amyloid imaging agent

This study describes the synthesis of a fluoroethylated derivative of [N-methyl-C]2-(40-methylaminophenyl)-6hydroxybenzothiazole ([C]6-OH-BTA-1; Pittsburgh Compound B (PIB)), an already established amyloid imaging agent. The [C]methylamino group of [C]6-OH-BTA-1 was formally replaced by a fluoroethyl group in a cold synthesis via N-alkylation of N-Boc-2-(40-aminophenyl)-6-(methoxyethoxymethoxy)benzothiazole with fluoroethyl tosylate. Subsequent deprotection gave the target compound 2-[40-(2-fluoroethyl)aminophenyl]-6-hydroxybenzothiazole (FBTA). In a radioligand competition assay on aggregated synthetic amyloid fibrils using N-[H-methyl]6-OH-BTA-1, 100 nM FBTA inhibited binding with 93 ± 1 and 83 ± 1% efficiency for Ab1–40 and Ab1–42, respectively. For the radiosynthesis a precursor carrying a tosylethyl moiety was prepared allowing the introduction of [F]fluoride via nucleophilic substitution with [F]tetra-nbutyl-ammonium fluoride (TBAF). Subsequent removal of all protecting groups was performed in a one-pot procedure followed by semi-preparative HPLC, delivering the target compound [F]FBTA in good radiochemical yield of 21% on average and radiochemical purity of X98% at EOS. In vitro autoradiography on human postmortem AD brain tissue slices showed intense cortical binding of [F]FBTA (1 nM), which was displaced in presence of 6-OH-BTA-1 (1 lM). Brain up-take was evaluated in wild-type (wt) mice with microPET imaging. Based on these results, [F]FBTA appears to be a suitable candidate tracer for amyloid imaging in humans.