Synthesis and evaluation of novel ¹⁸F labeled 2-pyridinylbenzoxazole and 2-pyridinylbenzothiazole derivatives as ligands for positron emission tomography (PET) imaging of β-amyloid plaques.

Abstract

A series of fluoro-pegylated (FPEG) 2-pyridinylbenzoxazole and 2-pyridinylbenzothiazole derivatives were synthesized and evaluated as novel β-amyloid (Aβ) imaging probes for PET. They displayed binding affinities for Aβ(1-42) aggregates that varied from 2.7 to 101.6 nM. Seven ligands with high affinity were selected for (18)F labeling. In vitro autoradiography results confirmed the high affinity of these radiotracers. In vivo biodistribution experiments in normal mice indicated that the radiotracers with a short FPEG chain (n = 1) displayed high initial uptake into and rapid washout from the brain. One of the 2-pyridinylbenzoxazole derivatives, [(18)F]-5-(5-(2-fluoroethoxy)benzo[d]oxazol-2-yl)-N-methylpyridin-2-amine ([(18)F]32) (K(i) = 8.0 ± 3.2 nM) displayed a brain(2min)/brain(60min) ratio of 4.66, which is highly desirable for Aβ imaging agents. Target specific binding of [(18)F]32 to Aβ plaques was validated by ex vivo autoradiographic experiment with transgenic model mouse. Overall, [(18)F]32 is a promising Aβ imaging agent for PET and merits further evaluation in human subjects.

• Authors: Mengchao Cui, Xuedan Wang, Pingrong Yu, Jinming Zhang, Zijing Li, Xiaojun Zhang, Yanping Yang, Masahiro Ono, Hongmei Jia, Hideo Saji, Boli Liu
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 55 Issue 21 Pg. 9283-96 (Nov 08 2012) ISSN: 1520-4804 [Electronic] United States
• PMID: 22974116 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-(5-(2-fluoroethoxy)benzo(d)oxazol-2-yl)-N-methylpyridin-2-amine
• Amyloid beta-Peptides
• Benzothiazoles
• Benzoxazoles
• Fluorine Radioisotopes
• Ligands
• Peptide Fragments
• Pyridines
• Radiopharmaceuticals
• amyloid beta-protein (1-42)
• Polyethylene Glycols

Topics

• Amyloid beta-Peptides (metabolism)
• Animals
• Autoradiography
• Benzothiazoles (chemical synthesis, chemistry, pharmacokinetics)
• Benzoxazoles (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
• Binding, Competitive
• Brain (metabolism)
• Drug Stability
• Fluorine Radioisotopes
• Humans
• Ligands
• Male
• Mice
• Mice, Transgenic
• Peptide Fragments (metabolism)
• Plaque, Amyloid (metabolism)
• Polyethylene Glycols (chemistry)
• Positron-Emission Tomography
• Pyridines (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
• Radioligand Assay
• Radiopharmaceuticals (chemical synthesis, chemistry, pharmacokinetics)
• Structure-Activity Relationship
• Tissue Distribution