Pharmacokinetics and amyloid plaque targeting ability of a novel peptide-based magnetic resonance contrast agent in wild-type and Alzheimer's disease transgenic mice.
A novel magnetic resonance (MR) imaging contrast agent based on a derivative of human amyloid beta (Abeta) peptide, Gd[N-4ab/Q-4ab]Abeta 30, was previously shown to cross the blood-brain barrier (BBB) and bind to amyloid plaques in Alzheimer's disease (AD) transgenic mouse (APP/PS1) brain. We now report extensive plasma and brain pharmacokinetics of this contrast agent in wild-type (WT) and in APP/PS1 mice along with a quantitative summary of various physiological factors that govern its efficacy. Upon i.v. bolus administration, (125)I-Gd[N-4ab/Q-4ab]Abeta 30 was rapidly eliminated from the plasma following a three-exponential disposition, which is saturable at higher concentrations. Nevertheless, the contrast agent exhibited rapid and nonsaturable absorption at the BBB. The brain pharmacokinetic profile of (125)I-Gd[N-4ab/Q-4ab]Abeta 30 showed a rapid absorption phase followed by a slower elimination phase. No significant differences were observed in the plasma or brain kinetics of WT and APP/PS1 animals. Emulsion autoradiography studies conducted on WT and APP/PS1 mouse brain after an i.v. bolus administration of (125)I-Gd[N-4ab/Q-4ab]Abeta 30 in vivo confirmed the brain pharmacokinetic data and also demonstrated the preferential localization of the contrast agent on the plaques for an extended period of time. These attributes of the contrast agent are extremely useful in providing an excellent signal/noise ratio during longer MR scans, which may be essential for obtaining a high resolution image. In conclusion, this study documents the successful plaque targeting of Gd[N-4ab/Q-4ab]Abeta 30 and provides crucial pharmacokinetic information to determine the dose, mode of administration, and scan times for future in vivo MR imaging of amyloid plaques in AD transgenic mice.
Kandimalla
Karunya K
KK
Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
Wengenack
Thomas M
TM
Curran
Geoffry L
GL
Gilles
Emily J
EJ
Poduslo
Joseph F
JF
D000544:Alzheimer Disease / Q000175:diagnosis* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003287:Contrast Media / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics*; D005682:Gadolinium / Q000737:chemistry; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007700:Kinetics; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D003287:Contrast Media; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D005682:Gadolinium