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

✍ Scribed by Ursula Berndt; Christian Stanetty; Thomas Wanek; Claudia Kuntner; Johann Stanek; Michael Berger; Martin Bauer; Gjermund Henriksen; Hans-Jürgen Wester; Herbert Kvaternik; Peter Angelberger; Christian Noe

• Publisher: John Wiley and Sons
• Year: 2008
• Tongue: French
• Weight: 266 KB
• Volume: 51
• Category: Article
• ISSN: 0022-2135
• DOI: 10.1002/jlcr.1476

✦ Synopsis

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.