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Enhancing PET Signal at Target Tissue in Vivo: Dendritic and Multimeric Tris(hydroxypyridinone) Conjugates for Molecular Imaging of αvβ3 Integrin Expression with Gallium-68
journal contribution
posted on 2016-11-29, 00:00 authored by Cinzia Imberti, Samantha Y. A. Terry, Carleen Cullinane, Fiona Clarke, Georgina H. Cornish, Nisha K. Ramakrishnan, Peter Roselt, Andrew P. Cope, Rodney J. Hicks, Philip J. Blower, Michelle T. MaTris(hydroxypyridinone)
chelators conjugated to peptides can rapidly complex the positron-emitting
isotope gallium-68 (68Ga) under mild conditions, and the
resulting radiotracers can delineate peptide receptor expression at
sites of diseased tissue in vivo. We have synthesized a dendritic
bifunctional chelator containing nine 1,6-dimethyl-3-hydroxypyridin-4-one
groups (SCN-HP9) that can coordinate up to three Ga3+ ions. This derivative has been conjugated to a trimeric
peptide (RGD3) containing three peptide groups that target
the αvβ3 integrin receptor. The
resulting dendritic compound, HP9-RGD3, can
be radiolabeled in 97% radiochemical yield at a 3-fold higher specific
activity than its homologues HP3-RGD and HP3-RGD3 that contain only a single metal binding site. PET
scanning and biodistribution studies show that [68Ga(HP9-RGD3)] demonstrates higher receptor-mediated tumor
uptake in animals bearing U87MG tumors that overexpress αvβ3 integrin than [68Ga(HP3-RGD)] and [68Ga(HP3-RGD3)]. However, concomitant nontarget organ retention of [68Ga(HP9-RGD3)] results in low tumor to nontarget
organ contrast in PET images. On the other hand, the trimeric peptide
homologue containing a single tris(hydroxypyridinone) chelator, [68Ga(HP3-RGD3)], clears nontarget organs
and exhibits receptor-mediated uptake in mice bearing tumors and in
mice with induced rheumatoid arthritis. PET imaging with [68Ga(HP3-RGD3)] enables clear delineation of
αvβ3 integrin receptor expression
in vivo.
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receptor-mediated tumor uptakeRGD 3nontarget organ retentiontrimeric peptide homologuedendritic bifunctional chelatorGahomologues HP 3positron-emitting isotope gallium -68SCN-HPα v β 3 integrin receptorexhibits receptor-mediated uptakeα v β 3 integrin receptor expressionnontarget organ contrastbiodistribution studies showpeptide receptor expressionα v β 3 Integrin ExpressionU 87MG tumorsEnhancing PET Signaloverexpress α v β 3 integrinmetal binding site
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