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

Abstract

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 Aβ₄₂.

Methods:

Microglial cell toxicity for cromolyn derivatives were determined in naive BV2 microglial cells. Microglial clearance assays were performed with Aβ₄₂ in naive BV2 microglial cell line and single cell clone BV2 line expressing CD33^WT. 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 Aβ₄₂ in naïve BV2 microglial cells. Derivative 4 increased Aβ₄₂ uptake in a dose-dependent manner and at 75μM resulted in a one-fold increase in Aβ₄₂ uptake in BV2-CD33^WT. 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 Aβ₄₂ in both naïve BV2 and BV2-CD33^WT 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 Aβ₄₂ in vivo and thereby serve as a therapeutic for the treatment and prevention of AD.