| First Author | Abrahamson EE | Year | 2021 |
| Journal | Nucl Med Biol | Volume | 92 |
| Pages | 85-96 | PubMed ID | 32471773 |
| Mgi Jnum | J:358099 | Mgi Id | MGI:7779726 |
| Doi | 10.1016/j.nucmedbio.2020.05.001 | Citation | Abrahamson EE, et al. (2021) Development of a PET radioligand selective for cerebral amyloid angiopathy. Nucl Med Biol 92:85-96 |
| abstractText | INTRODUCTION: Positron emission tomography (PET) using radiolabeled amyloid-binding compounds has advanced the field of Alzheimer's disease (AD) by enabling detection and longitudinal tracking of fibrillar amyloid-beta (Abeta) deposits in living people. However, this technique cannot distinguish between Abeta deposits in brain parenchyma (amyloid plaques) from those in blood vessels (cerebral amyloid angiopathy, CAA). Development of a PET radioligand capable of selectively detecting CAA would help clarify its contribution to global brain amyloidosis and clinical symptoms in AD and would help to characterize side-effects of anti-Abeta immunotherapies in AD patients, such as CAA. METHODS: A candidate CAA-selective compound (1) from a panel of analogues of the amyloid-binding dye Congo red was synthesized. The binding affinity to Abeta fibrils and lipophilicity of compound 1 were determined and selectivity for CAA versus parenchymal plaque deposits was assessed ex-vivo and in-vivo in transgenic APP/PS1 mice and in postmortem human brain affected with AD pathology. RESULTS: Compound 1 displays characteristics of Abeta binding dyes, such as thioflavin-S, in that it labels both parenchymal Abeta plaques and CAA when applied to histological sections from both a transgenic APP/PS1 mouse model of Abeta amyloidosis and AD brain. Thus, compound 1 lacks molecular selectivity to distinguish Abeta deposits in CAA from those in plaques. However, when administered to living APP/PS1 mice intravenously, compound 1 preferentially labels CAA when assessed using in-vivo two-photon microscopy and ex-vivo histology and autoradiography. CONCLUSION: We hypothesize that selectivity of compound 1 for CAA is attributable to its limited penetration of the blood-brain barrier due to the highly polar nature of the carboxylate moiety, thereby limiting access to parenchymal plaques and promoting selective in-vivo labeling of Abeta deposits in the vascular wall (i.e., "delivery selectivity"). |
