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Pharmacokinetics and amyloid plaque targeting ability of a novel peptide-based magnetic resonance contrast agent in wild-type and Alzheimer's disease transgenic mice.
J Pharmacol Exp Ther 2007; 322(2):541-9JP

Abstract

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.

Authors+Show Affiliations

Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17505020

Citation

Kandimalla, Karunya K., et al. "Pharmacokinetics and Amyloid Plaque Targeting Ability of a Novel Peptide-based Magnetic Resonance Contrast Agent in Wild-type and Alzheimer's Disease Transgenic Mice." The Journal of Pharmacology and Experimental Therapeutics, vol. 322, no. 2, 2007, pp. 541-9.
Kandimalla KK, Wengenack TM, Curran GL, et al. Pharmacokinetics and amyloid plaque targeting ability of a novel peptide-based magnetic resonance contrast agent in wild-type and Alzheimer's disease transgenic mice. J Pharmacol Exp Ther. 2007;322(2):541-9.
Kandimalla, K. K., Wengenack, T. M., Curran, G. L., Gilles, E. J., & Poduslo, J. F. (2007). Pharmacokinetics and amyloid plaque targeting ability of a novel peptide-based magnetic resonance contrast agent in wild-type and Alzheimer's disease transgenic mice. The Journal of Pharmacology and Experimental Therapeutics, 322(2), pp. 541-9.
Kandimalla KK, et al. Pharmacokinetics and Amyloid Plaque Targeting Ability of a Novel Peptide-based Magnetic Resonance Contrast Agent in Wild-type and Alzheimer's Disease Transgenic Mice. J Pharmacol Exp Ther. 2007;322(2):541-9. PubMed PMID: 17505020.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR 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. AU - Kandimalla,Karunya K, AU - Wengenack,Thomas M, AU - Curran,Geoffry L, AU - Gilles,Emily J, AU - Poduslo,Joseph F, Y1 - 2007/05/15/ PY - 2007/5/17/pubmed PY - 2007/9/21/medline PY - 2007/5/17/entrez SP - 541 EP - 9 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 322 IS - 2 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/17505020/Pharmacokinetics_and_amyloid_plaque_targeting_ability_of_a_novel_peptide_based_magnetic_resonance_contrast_agent_in_wild_type_and_Alzheimer's_disease_transgenic_mice_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17505020 DB - PRIME DP - Unbound Medicine ER -