Development of a PET radioligand selective for cerebral amyloid angiopathy

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 (A beta) deposits in living people. However, this technique cannot distinguish between A beta deposits in brain parenchyma (amyloid plaques) from those in blood vessels (cerebral amyloid angiopathy, CM). 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-A beta 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 A beta 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 Ali binding dyes, such as thioflavin-S, in that it labels both parenchymal Ali plaques and CAA when applied to histological sections from both a transgenic APP/PS1 mouse model of Ali amyloidosis and AD brain. Thus, compound 1 lacks molecular selectivity to distinguish A beta deposits in CAA from those in plaques. However, when administered to living APP / PS1 mice intravenously, compound 1 preferentially labels CM 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 A beta deposits in the vascular wall (i.e., "delivery selectivity"). Published by Elsevier Inc.