Synthesis of a [18F]fluorobenzothiazole as potential amyloid imaging agent

This study describes the synthesis of a fluoroethylated derivative of [N‐methyl‐¹¹C]2‐(4′‐methylaminophenyl)‐6‐hydroxybenzothiazole ([¹¹C]6‐OH‐BTA‐1; Pittsburgh Compound B (PIB)), an already established amyloid imaging agent. The [¹¹C]methylamino group of [¹¹C]6‐OH‐BTA‐1 was formally replaced by a fluoroethyl group in a cold synthesis via N‐alkylation of N‐Boc‐2‐(4′‐aminophenyl)‐6‐(methoxyethoxymethoxy)benzothiazole with fluoroethyl tosylate. Subsequent deprotection gave the target compound 2‐[4′‐(2‐fluoroethyl)aminophenyl]‐6‐hydroxybenzothiazole (FBTA). In a radioligand competition assay on aggregated synthetic amyloid fibrils using N‐[³H‐methyl]6‐OH‐BTA‐1, 100 nM FBTA inhibited binding with 93 ± 1 and 83 ± 1% efficiency for Aβ_1–40 and Aβ_1–42, respectively. For the radiosynthesis a precursor carrying a tosylethyl moiety was prepared allowing the introduction of [¹⁸F]fluoride via nucleophilic substitution with [¹⁸F]tetra‐n‐butyl‐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 [¹⁸F]FBTA in good radiochemical yield of 21% on average and radiochemical purity of ?98% at EOS. In vitro autoradiography on human postmortem AD brain tissue slices showed intense cortical binding of [¹⁸F]FBTA (1 nM), which was displaced in presence of 6‐OH‐BTA‐1 (1 µM). Brain up‐take was evaluated in wild‐type (wt) mice with microPET imaging. Based on these results, [¹⁸F]FBTA appears to be a suitable candidate tracer for amyloid imaging in humans. Copyright © 2008 John Wiley & Sons, Ltd.