2. Academic Validation
  3. Synthesis and characterization of gadolinium-Peptidomimetic complex as an αvβ3 integrin targeted MR contrast agent

Synthesis and characterization of gadolinium-Peptidomimetic complex as an αvβ3 integrin targeted MR contrast agent

  • Bioorg Med Chem Lett. 2015;25(10):2056-9. doi: 10.1016/j.bmcl.2015.03.092.
Young-Seung Kim 1,  Yang Zhou 1,  Henry Bryant Jr 2,  Diane E Milenic 1,  Kwamena E Baidoo 1,  Bobbi K Lewis 3,  Joseph A Frank 4,  Martin W Brechbiel 5
Affiliations

Affiliations

  • 1 Radioimmune & Inorganic Chemistry Section, ROB, NCI, NIH, 10 Center Drive, Building 10, Rm B3B69, Bethesda, MD 20892-1002, USA.
  • 2 Laboratory of Diagnostic Radiology Research (CC), NIH, Bethesda, MD, USA.
  • 3 Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD, USA.
  • 4 Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD, USA; National Institute of Biomedical Imaging and Bioengineering, NIH, Bethesda, MD, USA.
  • 5 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.
PMID: 25870133 DOI: 10.1016/j.bmcl.2015.03.092
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.

Keywords

Antagonist; DOTA; Gadolinium; Gd-153; Integrin α(v)β(3); MR imaging; Peptidomimetics.

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