P2-356: Imaging plaques in experimental animal models of AD with radioiodinated clioquinol

Abstract

Clioquinol (CQ), a derivative of 8–hydroxy quinoline, is a neutral, lipophilic, weak metal ion chelator. It readily penetrates the cell membrane, crosses the blood brain barrier and binds to Alzheimer's plaques rich in transition metals (Zn, Cu, Fe). The purpose of the study was to evaluate radioiodinated CQ to image plaques in an animal model of AD and transgenic mice. Aβ (1–42) peptide aggregates (1μg in 1 μl) were injected into the hippocampus of wild type BALB/c male mice by direct stereotaxis. The animals were allowed to recover for 8 days. Double transgenic mice for AD (APP & PS1) 12 months old were derived from (B6xC3H) F2 background. The double transgenic mice express a mutant human presenilin (DeltaE9) and a chimeric mouse/human amyloid precursor protein (APPswe). Experimental and age matched control animals were tested for cognitive function with Y maze. CQ precursor was radioiodinated (124I or 125I), using chloramine–T and purified by solvent extraction. The brains of the animals were taken out 1–2 hours after intravenous administration of 125I–CQ (1–5 μCi) and exposed to a Storage Phosphor Screen. The screens were imaged with a Cyclone® Phosphor Screen Imaging System (Perkin Elmer). Transgenic and control mice injected with 124I CQ (200–400 μCi) were imaged for 2 hours post i.v. administration, in UT Southwestern small animal PET imaging system. Then the brains were taken out and exposed to Phosphor Screen and imaged as before. The brain sections were stained with Congo red. The experimental animals had impaired cognitive function compared to age matched controls. The phosphor screen images showed localized uptake in the brains of experimental animals. Congo red staining confirmed the presence of the plaques. PET images showed higher uptake of the tracer in the brains of the transgenic animal compared to the control. Radioiodinated CQ showed binding specificity to AD plaques in vivo in brains of transgenic mice and mice injected with Aβ (1–42) peptide aggregates. 18F labeled tracer would likely give better quality images to 124I labeled agent. Plans are underway to synthesize 18F labeled CQ and other analogs for imaging AD plaques.