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

Abstract This study describes the synthesis of a fluoroethylated derivative of [ N ‐methyl‐ 11 C]2‐(4′‐methylaminophenyl)‐6‐hydroxybenzothiazole ([ 11 C]6‐OH‐BTA‐1; Pittsburgh Compound B (PIB)), an already established amyloid imaging agent. The [ 11 C]methylamino group of [ 11 C]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 ‐[ 3 H‐methyl]6‐OH‐BTA‐1, 100 nM FBTA inhibited binding with 93 ± 1 and 83 ± 1% efficiency for A β 1–40 and A β 1–42 , respectively. For the radiosynthesis a precursor carrying a tosylethyl moiety was prepared allowing the introduction of [ 18 F]fluoride via nucleophilic substitution with [ 18 F]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 [ 18 F]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 [ 18 F]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, [ 18 F]FBTA appears to be a suitable candidate tracer for amyloid imaging in humans. Copyright © 2008 John Wiley & Sons, Ltd.