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IC‐O3‐02: Development of a CAA‐specific amyloid imaging tracer
Author(s) -
Han ByungHee,
Chu Wenhua,
Xu Jinbin,
Mach Robert,
Zipfel Gregory
Publication year - 2012
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2012.05.029
Subject(s) - cerebral amyloid angiopathy , senile plaques , pittsburgh compound b , amyloid (mycology) , pathology , chemistry , medicine , alzheimer's disease , dementia , disease
Background: Cerebral amyloid angiopathy (CAA) is a well recognized cause of lobar cerebral hemorrhage, ischemic stroke, and cognitive dysfunction both in AD and non-AD patient populations. Yet to date only “possible” or “probable” diagnosis of CAA has been achievable without obtaining pathological tissue via brain biopsy or at autopsy. Though amyloid tracers labeled with positron-emitting radioligands have shown promise for non-invasive amyloid imaging in AD patients, they have been unable to clarify whether the observed amyloid load represents neuritic plaques vs. CAA due to the low resolution of PET imaging and the almost equal affinity of these tracers for both vascular and parenchymal amyloid. Recently, we demonstrated that phenoxazine analogs preferentially bind CAA over neuritic plaques in postmortem AD brain tissues as well as in aged Tg2576 mice (Han et al, Molecular Neurodegeneration 6:86, 2011). Though the molecular basis underlying their selective binding to CAA remains elusive, this unique binding specificity suggests that this type of compound has great potential as a CAA-specific amyloid tracer that will permit non-invasive diagnosis of CAA, quantitation of CAA severity, and monitoring of CAA progression over time. Methods: To further explore this possibility, we synthesized a series of new phenoxazine analogs based on our preliminary structure-activity relationship data. We determined the binding affinity (Ki values) of these novel compounds on CAA isolated from Tg2576 mice utilizing a competitive binding assay system with a [3H]phenoxazine ligand. We next performed an in situ competitive binding assay to determine their selective binding affinity for CAA over neuritic plaques in brain tissues of aged Tg2576 mice having both CAA deposits and neuritic plaques. The lipophilicity of phenoxazine derivatives was determined by octanol-water coefficient to predict their brain accessibility. Results: We found that phenoxazine derivatives, in particular 5-5, revealed enhanced binding affinity for CAA as compared with the parental compound. More importantly, synthesized phenoxazine analogs preserved the preferential binding affinity for CAA over neuritic plaques. Conclusions: These results strongly suggest that phenoxazine analogs provide great potential for development of a CAA-specific amyloid tracer that would be a major diagnostic step forward for this frequent (but often under-diagnosed) condition.