RT Journal Article
SR Electronic
T1 Pharmacokinetics and Amyloid Plaque Targeting Ability of a Novel Peptide-Based Magnetic Resonance Contrast Agent in Wild-Type and Alzheimer's Disease Transgenic Mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 541
OP 549
DO 10.1124/jpet.107.119883
VO 322
IS 2
A1 Karunya K. Kandimalla
A1 Thomas M. Wengenack
A1 Geoffry L. Curran
A1 Emily J. Gilles
A1 Joseph F. Poduslo
YR 2007
UL http://jpet.aspetjournals.org/content/322/2/541.abstract
AB A novel magnetic resonance (MR) imaging contrast agent based on a derivative of human amyloid β (Aβ) peptide, Gd[N-4ab/Q-4ab]Aβ 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, 125I-Gd[N-4ab/Q-4ab]Aβ 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 125I-Gd[N-4ab/Q-4ab]Aβ 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 125I-Gd[N-4ab/Q-4ab]Aβ 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]Aβ 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. The American Society for Pharmacology and Experimental Therapeutics