Enhancing PET Signal at Target Tissue in Vivo: Dendritic and Multimeric Tris(hydroxypyridinone) Conjugates for Molecular Imaging of α(v)β(3) Integrin Expression with Gallium-68

[Image: see text] Tris(hydroxypyridinone) chelators conjugated to peptides can rapidly complex the positron-emitting isotope gallium-68 ((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(9)) that can coordinate up to three Ga(3+) ions. This derivative has been conjugated to a trimeric peptide (RGD(3)) containing three peptide groups that target the α(v)β(3) integrin receptor. The resulting dendritic compound, HP(9)-RGD(3), can be radiolabeled in 97% radiochemical yield at a 3-fold higher specific activity than its homologues HP(3)-RGD and HP(3)-RGD(3) that contain only a single metal binding site. PET scanning and biodistribution studies show that [(68)Ga(HP(9)-RGD(3))] demonstrates higher receptor-mediated tumor uptake in animals bearing U87MG tumors that overexpress α(v)β(3) integrin than [(68)Ga(HP(3)-RGD)] and [(68)Ga(HP(3)-RGD(3))]. However, concomitant nontarget organ retention of [(68)Ga(HP(9)-RGD(3))] 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, [(68)Ga(HP(3)-RGD(3))], clears nontarget organs and exhibits receptor-mediated uptake in mice bearing tumors and in mice with induced rheumatoid arthritis. PET imaging with [(68)Ga(HP(3)-RGD(3))] enables clear delineation of α(v)β(3) integrin receptor expression in vivo.