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

Abstract

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.

Palladium‐Catalyzed Allylic Fluorination

“…Our results are summarized in Table 3. Various 2-substituted propenyl fluorides (19)(20)(21), which are structurally related to 2, were obtained in high yields (> 80 %; entries 1-4). The reaction to form the parent compound 22 is comparably efficient, but the volatility of this product attenuates the yield of isolated product (entry 5).…”

Synthesis, resolution, and in vitro evaluation of three vesicular acetylcholine transporter ligands and evaluation of the lead fluorine-18 radioligand in a nonhuman primate

“…Otherwise production of 2-oxazolidinone or vinyl 4-methylbenzenesulfonate may be the predominate product. 31 By similar strategy, the standard reference for the radiolabeling intermediate (±)- 20 was obtained by the reaction of compound (±)- 18 with the 2-fluoroethyl tosylate. Since the minus enantiomer was more potent for VAChT, we also conducted chiral separation of compound (±)- 15 using a Chiralcel OD column to obtain the corresponding resolved minus compound (−)- 15 .…”

“…Others have reported that nitrogen-containing tosylate is prone to decompose under storage and makes the reproducibility and reliability for radiolabeling uncertain. 31 We reported a two-pot, two-step synthesis of [ 18 F]VAT in a cGMP facility that had good reproducibility and afforded high quality [ 18 F]VAT suitable for clinic investigation; this procedure improved the radiochemical yield and avoided decomposition of the precursor. 21 Therefore, we decided to introduce the [ 18 F]fluoroethyl moiety in situ starting with the enantiomeric precursor (−)- 18 .…”

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

“…Moving the [ 18 F]fluoroethoxy substituent of 62 from the 6-position to the 3'-position resulted in a low binding affinity for Aβ and an inability to stain plaques in postmortem AD brain [63]. In compound 63 , the [ 11 C]methylamino group of [ 11 C] 56c was replaced by a [ 18 F]fluoroethylamino group, and, while this compound showed better binding affinity than 56c , its brain pharmacokinetics were not as good [64]. Compound 64 also showed promising results in whole-body biodistribution and radiation dosimetry studies [65].…”