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 language | English (US) |
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Pages (from-to) | 647-664 |
Number of pages | 18 |
Journal | Journal of Labelled Compounds and Radiopharmaceuticals |
Volume | 45 |
Issue number | 8 |
DOIs | |
State | Published - 2002 |
Externally published | Yes |
Keywords
- Alzheimer's disease
- Brain uptake
- C-labelling
- NOR-beta transgenic mouse model
- β-amyloid
ASJC Scopus subject areas
- Analytical Chemistry
- Biochemistry
- Radiology Nuclear Medicine and imaging
- Drug Discovery
- Spectroscopy
- Organic Chemistry