Noninvasive imaging of peripherally injected Alzheimer's disease type synthetic A beta amyloid in vivo.
The pathological hallmark of Alzheimer's disease (AD) is accumulation in the brain of amyloid composed of the 40-mer peptide A beta. Many fundamental questions about the biology of (AD) remain unanswered because there is currently no method of quantifying A beta amyloid in vivo. A noninvasive method of detecting and quantifying A beta amyloid in vivo would have wide application for the premortem diagnosis of AD and the efficient evaluation of candidate therapeutics aimed at inhibiting the formation and growth of A beta amyloid. Taking advantage of the extraordinarily high affinity of A beta for itself, we have synthesized an N'-terminal diethylenetriaminepentaacetic acid (DTPA) derivative of A beta possessing the kinetic activity and specificity for A beta amyloid desired of a probe to be used for noninvasive imaging. DTPA-A beta(3-40) is readily labeled with (111)InOAc(3) to yield a stable probe with exquisite specificity for naturally occurring and synthetic A beta amyloid in vitro. Moreover, (111)In-DTPA-A beta(3-40), administered intravascularly can specifically deposit onto and label previously injected synthetic A beta amyloid and be imaged in vivo with a gamma camera. The present results demonstrate the design, synthesis, and use of an A beta amyloid-specific probe and methods for its use as a noninvasive imaging agent. In vivo imaging of A beta amyloid represents an important step toward the development of biochemically based objective tools for the assessment of progression of AD and efficacy of potential therapeutics.
Marshall
Jeffrey R
JR
Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, 231 Albert B. Sabin Way, Cincinnati, Ohio 45267, USA.
Stimson
Evelyn R
ER
Ghilardi
Joseph R
JR
Vinters
Harry V
HV
Mantyh
Patrick W
PW
Maggio
John E
JE
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D000818:Animals; D001921:Brain / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007205:Indium Radioisotopes; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D004369:Pentetic Acid / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013194:Staining and Labeling
D016229:Amyloid beta-Peptides; D007205:Indium Radioisotopes; D004369:Pentetic Acid