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

Tris(hydroxypyridinone) chelators conjugated to peptides can rapidly complex the positron-emitting isotope gallium-68 (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-HP) that can coordinate up to three Ga ions. This derivative has been conjugated to a trimeric peptide (RGD) containing three peptide groups that target the αβ integrin receptor. The resulting dendritic compound, HP-RGD, can be radiolabeled in 97% radiochemical yield at a 3-fold higher specific activity than its homologues HP-RGD and HP-RGD that contain only a single metal binding site. PET scanning and biodistribution studies show that [Ga(HP-RGD)] demonstrates higher receptor-mediated tumor uptake in animals bearing U87MG tumors that overexpress αβ integrin than [Ga(HP-RGD)] and [Ga(HP-RGD)]. However, concomitant nontarget organ retention of [Ga(HP-RGD)] 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, [Ga(HP-RGD)], clears nontarget organs and exhibits receptor-mediated uptake in mice bearing tumors and in mice with induced rheumatoid arthritis. PET imaging with [Ga(HP-RGD)] enables clear delineation of αβ integrin receptor expression in vivo.