Molecular Targeting of Alzheimer's Amyloid Plaques for Contrast-Enhanced MRI

Smart molecular probes for both diagnostic and therapeutic purposes are expected to provide significant advances in clinical medicine and biomedical research. We describe such a probe that targets beta-amyloid plaques of Alzheimer's disease and is detectable by magnetic resonance imaging (MRI) because of contrast imparted by gadolinium labeling. Three properties essential for contrast enhancement of beta-amyloid plaques on MRI exist in this smart molecular probe, putrescine-gadolinium-amyloid-beta peptide: (1) transport across the blood-brain barrier following intravenous injection conferred by the polyamine moiety, (2) binding to plaques with molecular specificity by putrescine-amyloid-beta, and (3) magnetic resonance imaging contrast by gadolinium. MRI was performed on ex vivo tissue specimens at 7 T at a spatial resolution approximating plaque size (62.5 microm(3)), in order to prove the concept that the probe, when administered intravenously, can selectively enhance plaques.

The plaque-to-background tissue contrast-to-noise ratio, which was precisely correlated with histologically stained plaques, was enhanced more than nine-fold in regions of cortex and hippocampus following intravenous administration of this probe in AD transgenic mice. Continuing engineering efforts to improve spatial resolution are underway in MRI, which may enable in vivo imaging at the resolution of individual plaques with this or similar contrast probes. This could enable early diagnosis and also provide a direct measure of the efficacy of anti-amyloid therapies currently being developed.

Poduslo JF, Curran GL, Peterson JA, McCormick DJ, Fauq AH, Khan MA, Wengenack TM., Design and chemical synthesis of a magnetic resonance contrast agent with enhanced in vitro binding, high blood-brain barrier permeability, and in vivo targeting to Alzheimer's disease amyloid plaques. Biochemistry. 2004 May 25;43(20):6064-75.

Poduslo JF, Wengenack TM, Curran GL, Wisniewski T, Sigurdsson EM, Macura SI, Borowski BJ, Jack CR Jr., Molecular targeting of Alzheimer's amyloid plaques for contrast-enhanced magnetic resonance imaging. Neurobiol Dis. 2002 Nov;11(2):315-29.