title: Synthesis and characterization of gadolinium-Peptidomimetic complex as an αvβ3 integrin targeted MR contrast agent.
abstract: There is growing interest in small and rigid peptidomimetic αvβ3 integrin antagonists that are readily synthesized and characterized and amenable to physiological conditions. Peptidomimetic 4-[2-(3,4,5,6-tetrahydropyrimidine-2-ylamino)ethyloxy]benzoyl-2-[N-(3-amino-neopenta-1-carbamyl)]-aminoethylsulfonyl-amino-β-alanine (IAC) was successfully conjugated to DOTA, complexed with Gd(III) and radiolabeled with (153)Gd. Radioassay results demonstrated specificity of the labeled conjugate by blocking ∼95% binding with the addition of a 50-fold molar excess of cold IAC to the reaction solution. Relaxometry was used to support the hypothesis that the specificity of the Gd-peptidomimetic targeting αvβ3 integrin would increase the contrast and therefore enhance the sensitivity of an MRI scan of αvβ3 integrin positive tissues. Magnetic resonance imaging of cell pellets (M21 human melanoma) was also performed, and the images clearly show that cells reacted with Gd(III)-DOTA-IAC display a brighter image than cells without the Gd(III)-DOTA-IAC contrast agent. In addition, Gd(III)-DOTA-IAC and IAC, with IC50 of 300nM and 230nM, respectively, are 2.1 and 2.7 times more potent than c(RGDfK) whose IC50 is 625nM. This promising preliminary data fuels further investigation of DOTA-IAC conjugates for targeting tumor associated angiogenesis and αvβ3 integrin positive tumors using magnetic resonance imaging.
authors: Radioimmune & Inorganic Chemistry Section, ROB, NCI, NIH, 10 Center Drive, Building 10, Rm B3B69, Bethesda, MD 20892-1002, USA.
authors: Young-Seung
authors: YS
authors: Kim
authors: Radioimmune & Inorganic Chemistry Section, ROB, NCI, NIH, 10 Center Drive, Building 10, Rm B3B69, Bethesda, MD 20892-1002, USA.
authors: Yang
authors: Y
authors: Zhou
authors: Laboratory of Diagnostic Radiology Research (CC), NIH, Bethesda, MD, USA.
authors: Henry
authors: H
authors: Bryant
authors: Radioimmune & Inorganic Chemistry Section, ROB, NCI, NIH, 10 Center Drive, Building 10, Rm B3B69, Bethesda, MD 20892-1002, USA.
authors: Diane E
authors: DE
authors: Milenic
authors: Radioimmune & Inorganic Chemistry Section, ROB, NCI, NIH, 10 Center Drive, Building 10, Rm B3B69, Bethesda, MD 20892-1002, USA.
authors: Kwamena E
authors: KE
authors: Baidoo
authors: Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD, USA.
authors: Bobbi K
authors: BK
authors: Lewis
authors: Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD, USA; National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, MD, USA.
authors: Joseph A
authors: JA
authors: Frank
authors: Radioimmune & Inorganic Chemistry Section, ROB, NCI, NIH, 10 Center Drive, Building 10, Rm B3B69, Bethesda, MD 20892-1002, USA. Electronic address: martinwb@mail.nih.gov.
authors: Martin W
authors: MW
authors: Brechbiel
mesh_terms: D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003287:Contrast Media / Q000138:chemical synthesis* / Q000737:chemistry; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry; D005682:Gadolinium / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D039302:Integrin alphaVbeta3 / Q000737:chemistry*; D008279:Magnetic Resonance Imaging; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D003287:Contrast Media; D056831:Coordination Complexes; D039302:Integrin alphaVbeta3; D057786:Peptidomimetics; D005682:Gadolinium
keywords: Antagonist; DOTA; Gadolinium; Gd-153; Integrin α(v)β(3); MR imaging; Peptidomimetics