Synthesis and 11c-labelling of (E,E)-1-(3′,4′-dihydroxystyryl)-4-(3′-methoxy-4 ′-hydroxystyryl) benzene for PET imaging of amyloid deposits

Yanming Wang, Chester A. Mathis, Guo Feng Huang, Daniel Holt, Manik L. Debnath, William E. Klunk

Research output: Contribution to journalArticle

Abstract

Carboxylic acid derivatives of the amyloid-binding dye Congo red do not enter the brain well and are thus unable to serve as in vivo amyloid-imaging agents. A neutral amyloid probe, (E,E)-1-(3′,4′-dihydroxystyryl)-4-(3′-methoxy-4 ′-hydroxystyryl)benzene (3), devoid of any carboxylate groups has been designed and synthesized via a 12-step reaction sequence with a total yield of 30%. The unsymmetric compound 3 has also been labelled with C-11 via [11C]methyl iodide ([11C]CH3I) methylation of a symmetric 4,4′-dimesyl protected precursor followed by deprotection. Preliminary evaluation indicated that compound 3 selectively stained plaques and neurofibrillary tangles in post-mortem AD brain, and exhibited good binding affinity (Ki = 38 ± 8 nM) for Aβ(1-40) fibrils in vitro. In vivo pharmacokinetic studies indicated that [11C]3 exhibited higher brain uptake than its carboxylic acid analogs and good clearance from normal control mouse brain. [11C]3 also exhibited specific in vivo binding to pancreatic amyloid deposits in the NOR-beta transgenic mouse model. These results justify further investigation of 3 and similar derivatives as surrogate markers for in vivo quantitation of amyloid deposits.

Original languageEnglish (US)
Pages (from-to)647-664
Number of pages18
JournalJournal of Labelled Compounds and Radiopharmaceuticals
Volume45
Issue number8
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Amyloid Plaques
Benzene
Amyloid
Labeling
Deposits
Brain
Imaging techniques
Carboxylic Acids
Congo Red
Neurofibrillary Tangles
Derivatives
Methylation
Pharmacokinetics
Transgenic Mice
Coloring Agents
Biomarkers

Keywords

  • β-amyloid
  • C-labelling
  • Alzheimer's disease
  • Brain uptake
  • NOR-beta transgenic mouse model

ASJC Scopus subject areas

  • Analytical Chemistry
  • Drug Discovery
  • Organic Chemistry
  • Clinical Biochemistry
  • Molecular Medicine
  • Pharmacology

Cite this

Synthesis and 11c-labelling of (E,E)-1-(3′,4′-dihydroxystyryl)-4-(3′-methoxy-4 ′-hydroxystyryl) benzene for PET imaging of amyloid deposits. / Wang, Yanming; Mathis, Chester A.; Huang, Guo Feng; Holt, Daniel; Debnath, Manik L.; Klunk, William E.

In: Journal of Labelled Compounds and Radiopharmaceuticals, Vol. 45, No. 8, 2002, p. 647-664.

Research output: Contribution to journalArticle

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