Evaluation of Fluorinated Cromolyn Derivatives as Potential Therapeutics for Alzheimer's Disease.

Background Cromolyn is an anti-neuroinflammatory modulator with a multifactorial mechanism of action that has been shown to inhibit amyloid-β (Aβ) aggregation and enhance microglial uptake and clearance of Aβ. Objective We report the effects of fluoro-cromolyn derivatives on microglial cell toxicity and microglial clearance of Aβ 42. Methods Microglial cell toxicity for cromolyn derivatives were determined in naive BV2 microglial cells. Microglial clearance assays were performed with Aβ 42 in naive BV2 microglial cell line and single cell clone BV2 line expressing CD33WT. PET imaging was performed for three F-18 analogs in a rhesus macaque. Results All compounds but derivative 8 exhibited low microglial cell toxicity. Cromolyn 1 and derivatives 2, 4, and 7 displayed an increased uptake on Aβ 42 in naive BV2 microglial cells. Derivative 4 increased Aβ 42 uptake in a dose-dependent manner and at 75μM resulted in a one-fold increase in Aβ 42 uptake in BV2-CD33WT. PET imaging for three [18F]cromolyn analogs revealed the order of brain tracer penetration to be 4a > 10 > 2a. Tracer 4a exhibited enhanced uptake in areas of high perfusion (putamen, grey matter, and cerebellum) and lower signal in areas of lower perfusion (caudate, thalamus, and white matter). Conclusion Substantial uptake of Aβ 42 in both naive BV2 and BV2-CD33WT cells observed with 4 indicate conversion of microglial cells from a pro-inflammatory to an activation state favoring Aβ phagocytosis/clearance. These findings suggest that a fluoro-cromolyn analog could reduce fibril-prone Aβ 42in vivo and thereby serve as a therapeutic for the treatment and prevention of AD.