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

• Published in: Journal of labelled compounds & radiopharmaceuticals Vol. 51; no. 3; pp. 137 - 145
• Main Authors: Berndt, Ursula, Stanetty, Christian, Wanek, Thomas, Kuntner, Claudia, Stanek, Johann, Berger, Michael, Bauer, Martin, Henriksen, Gjermund, Wester, Hans-Jürgen, Kvaternik, Herbert, Angelberger, Peter, Noe, Christian
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 15-03-2008; Wiley
• Subjects: [11C] BTA; [18 F] FBTA; Alzheimer's disease; amyloid; Biological and medical sciences; Contrast media. Radiopharmaceuticals; Medical sciences; PET; Pharmacology. Drug treatments; Fluorine 18; Alzheimer disease; [11C] BTA; Central nervous system; Carbon Isotopes; [18F] FBTA; Degenerative disease; Radioisotopic product; Chemical synthesis; Alzheimer's disease; Human; Fluorine Isotopes; Rodentia; Glycoprotein; Postmortem; Autopsy material; In vitro; Protein; Autoradiography; In vivo; Vertebrata; Mammalia; amyloid; Mouse; β Amyloid protein; Animal; Positron emission tomography; PET
• ISSN: 0362-4803; 1099-1344
• DOI: 10.1002/jlcr.1476

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 Aβ1–40 and Aβ1–42, 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.
[18F]FBTA, a fluoroethylated derivative of [11C]6‐OH‐BTA‐1 (Pittsburgh Compound B (PIB)), was synthesised as potential amyloid imaging agent. In the cold synthesis a fluoroethyl group was introduced via N‐alkylation. In the radiosynthesis [18F]fluoride was introduced in a precursor carrying a tosylethyl moiety via nucleophilic substitution. Binding to Aβ plaques was evaluated by a radioligand competition assay and by in vitro autoradiography using human postmortem AD brain tissue slices. Brain up‐take was evaluated in wild‐type mice by means of microPET imaging. Copyright © 2008 John Wiley & Sons, Ltd.