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-beta (A beta) aggregation and enhance microglial uptake and clearance of A beta. Objective: We report the effects of fluoro-cromolyn derivatives on microglial cell toxicity and microglial clearance of A beta(42). Methods: Microglial cell toxicity for cromolyn derivatives were determined in naive BV2 microglial cells. Microglial clearance assays were performed with A beta(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 lowmicroglial cell toxicity. Cromolyn 1 and derivatives 2, 4, and 7 displayed an increased uptake on A beta(42) in naive BV2 microglial cells. Derivative 4 increased A beta(42) uptake in a dose-dependent manner and at 75 mu M resulted in a one-fold increase in A beta(42) uptake in BV2-CD33(WT). PET imaging for three [F-18]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 A beta(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 A beta phagocytosis/clearance. These findings suggest that a fluoro-cromolyn analog could reduce fibril-prone A beta 42 in vivo and thereby serve as a therapeutic for the treatment and prevention of AD.