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New 18F labeled fused five and six-membered heterocyclic compounds with benzylic fluoride as β-amyloid (Aβ) plaque imaging

¹ Nuclear Medicine, Seoul National University College of Medicine, Seoul, South Korea

568

Objectives: Fused five and six-membered heterocyclic compounds have high affinity to Aβ plaques. We synthesized novel benzothiazole, benzoxazole, benzothiophene and benzofuran derivatives containing benzylic fluoride group and compared their affinity to Aβ plaques and brain uptakes in normal mice.

Methods: To evaluate the affinity to Aβ plaque, 2-(4’-fluoromethyl)phenyl-1,3-benzothiazole (1), 2-(4’-fluoromethyl)phenyl-1,3-benzoxazole (2), 2-(4’-fluoromethyl)phenylbenzo[b]thiophene (3), and 2-(4’-fluoromethyl)phenylbenzo[b]furan (4) were synthesized. The Ki values of the synthesized compounds were evaluated by competition against 2-(3’-[125I]iodo-4’-methylaminophenyl)benzothiazole binding to Aβ(1-40) and Aβ(1-42) aggregates. Tosylated precursors for 18F labeling, were synthesized and labeled with 18F. The labeling efficiency was checked by radio-TLC. Biodistribution of [18F]1 was performed in ICR-mice (male, n=9, 37.4±3.5 g).

Results: The chemical structures of synthesized compounds were checked by 1H NMR. The Ki values of 1, 2, 3 and 4 for Aβ(1-40) aggregates were 47.3±17.5, 108.7±49.7, 5.9±5.6 and 34.2±25.4 nM, respectively, and for Aβ(1-42) aggregates were 38.3±39.2, 65.8±28.4, 1.1±0.1 and 5.6±3.7 nM, respectively. In the Biodistribution study, the brain uptake of [18F]1 was 5.6±0.3% ID/g at 2 min, 1.6±0.5% ID/g at 30 min and 1.0±0.1 % ID/g at 60 min after tail vein injection. The brain uptake ratio between 2 min and 60 min was 5.6±0.3.

Conclusions: Fused five and six-membered heterocycic compounds with benzylic fluoride showed moderate to high binding affinity to Aβ aggregates, and 2-(4’-[18F]fluoromethylphenyl)benzothiazole ([18F]1) showed high initial uptake and fast wash-out rate in normal mouse brain.

This Article Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lee, Y.-S. Articles by Lee, M. PubMed Articles by Lee, Y.-S. Articles by Lee, M.