Resorufin analogs preferentially bind cerebrovascular amyloid: potential use as imaging ligands for cerebral amyloid angiopathy

Molecular Neurodegeneration

Gregory J Zipfel⁴  Robert H Mach¹  Wenhua Chu¹  Jacob K Greenberg⁵  David H Kim⁵  Eric Milner³  Ananth K Vellimana⁵  Meng-liang Zhou⁵  Byung Hee Han² 

[1] Division of Radiological Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA;Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA;Program in Neuroscience, Washington University Division of Biology and Biomedical Sciences, St. Louis, MO 63110, USA;Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA;Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA

关键词: phenoxazines;    resorufin;    tracer;    amyloid imaging;    positron emission tomography;    amyloid beta;    diagnosis;    dementia;    Alzheimer's disease;    Cerebral amyloid angiopathy;   

Others  :  863984
DOI  :  10.1186/1750-1326-6-86

 received in 2011-10-10, accepted in 2011-12-22,  发布年份 2011

【 摘 要 】

Background

Cerebral amyloid angiopathy (CAA) is characterized by deposition of fibrillar amyloid β (Aβ) within cerebral vessels. It is commonly seen in the elderly and almost universally present in patients with Alzheimer's Disease (AD). In both patient populations, CAA is an independent risk factor for lobar hemorrhage, ischemic stroke, and dementia. To date, definitive diagnosis of CAA requires obtaining pathological tissues via brain biopsy (which is rarely clinically indicated) or at autopsy. Though amyloid tracers labeled with positron-emitting radioligands such as [¹¹C]PIB have shown promise for non-invasive amyloid imaging in AD patients, to date they have been unable to clarify whether the observed amyloid load represents neuritic plaques versus CAA due in large part to the low resolution of PET imaging and the almost equal affinity of these tracers for both vascular and parenchymal amyloid. Therefore, the development of a precise and specific non-invasive technique for diagnosing CAA in live patients is desired.

Results

We found that the phenoxazine derivative resorufin preferentially bound cerebrovascular amyloid deposits over neuritic plaques in the aged Tg2576 transgenic mouse model of AD/CAA, whereas the congophilic amyloid dye methoxy-X34 bound both cerebrovascular amyloid deposits and neuritic plaques. Similarly, resorufin-positive staining was predominantly noted in fibrillar Aβ-laden vessels in postmortem AD brain tissues. Fluorescent labeling and multi-photon microscopy further revealed that both resorufin- and methoxy-X34-positive staining is colocalized to the vascular smooth muscle (VSMC) layer of vessel segments that have severe disruption of VSMC arrangement, a characteristic feature of CAA. Resorufin also selectively visualized vascular amyloid deposits in live Tg2576 mice when administered topically, though not systemically. Resorufin derivatives with chemical modification at the 7-OH position of resorufin also displayed a marked preferential binding affinity for CAA, but with enhanced lipid solubility that indicates their use as a non-invasive imaging tracer for CAA is feasible.

Conclusions

To our knowledge, resorufin analogs are the fist class of amyloid dye that can discriminate between cerebrovascular and neuritic forms of amyloid. This unique binding selectivity suggests that this class of dye has great potential as a CAA-specific amyloid tracer that will permit non-invasive detection and quantification of CAA in live patients.

【 授权许可】

   
2011 Han et al; licensee BioMed Central Ltd.

【 图 表 】

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