99mTc-MAMA-chrysamine G, a probe for beta-amyloid protein of Alzheimer's disease

Chrysamine G (CG), an analogue of Congo red, is known to bind in vitro to the beta-amyloid protein (A beta 10-43) and to homogenates of several regions of the brain of Alzheimer's disease (AD) patients. We synthesised a conjugate of 2-(acetamido)-CG with a bis-S-trityl protected monoamide-monoaminedithiol (MAMA-Tr-2) tetraligland, which was efficiently deprotected and la belled with a 75% yield with technetium-99m, to obtain Tc-99m-MAMA-CG. In mice, Tc-99m-MAMA-CG was cleared mainly by the hepatobiliary system, resulting in a fast blood clearance. Brain uptake of Tc-99m-MAMA-CG was low. Co-injection with the blood pool tracer iodine-125 human serum albumin (I-125-HSA) demonstrated a brain/blood activity ratio for Tc-99m-MAMA-CG that was significantly higher than that for I-125-HSA (t test for dependent samples, P<0.02), indicating the ability of 99mTc-MAMA-CG to cross the blood-brain barrier. In vitro autoradiography demonstrated pronounced binding of Tc-99m-MAMA-CG to beta-amyloid deposits in autopsy sections of the parietal and occipital cortex of an AD patient as compared with controls. Adding 10 mu M Congo red during incubation displaced the binding of Tc-99m-MAMA-CG. Congo red staining and autoradiography identified the same lesions. Tc-99m-MAMA-CG seems to bind selectively to beta-amyloid deposition in human brain parenchyma and blood vessels in vitro and thus might be a lead compound for further development of a useful tracer agent for the in vivo diagnosis of Alzheimer's disease.