Enhancing PET Signal at Target Tissue in Vivo: Dendritic and Multimeric Tris(hydroxypyridinone) Conjugates for Molecular Imaging of αvβ3 Integrin Expression with Gallium-68

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• 作者：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. Ma
• 刊名：Bioconjugate Chemistry
• 出版年：2017
• 出版时间：February 15, 2017
• 年：2017
• 卷：28
• 期：2
• 页码：481-495
• 全文大小：707K
• ISSN：1520-4812

文摘

Tris(hydroxypyridinone) chelators conjugated to peptides can rapidly complex the positron-emitting isotope gallium-68 (p>68p>Ga) 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 Gap>3+p> ions. This derivative has been conjugated to a trimeric peptide (RGD₃) containing three peptide groups that target the α_vβ₃ 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 [p>68p>Ga(HP₉-RGD₃)] demonstrates higher receptor-mediated tumor uptake in animals bearing U87MG tumors that overexpress α_vβ₃ integrin than [p>68p>Ga(HP₃-RGD)] and [p>68p>Ga(HP₃-RGD₃)]. However, concomitant nontarget organ retention of [p>68p>Ga(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, [p>68p>Ga(HP₃-RGD₃)], clears nontarget organs and exhibits receptor-mediated uptake in mice bearing tumors and in mice with induced rheumatoid arthritis. PET imaging with [p>68p>Ga(HP₃-RGD₃)] enables clear delineation of α_vβ₃ integrin receptor expression in vivo.