Abstract
Tris(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.
Highlights
Peptide-based imaging agents in nuclear medicine have tremendous utility in diagnosis, prognosis, and selection of therapeutic regimes for patients
Subsequent removal of the phthalimide group furnished 4, which possesses a primary amine that can be further functionalized for attachment to biomolecules. This species was converted to a phenyl isothiocyanate by reacting it with an excess of p-phenylene diisothiocyanate, resulting in 5, which was isolated via semipreparative reverse phase High-performance liquid chromatography (HPLC)
Compound SCN-HP9 was obtained upon deprotection of the benzyl-protected hydroxypyridinone groups by reaction of 5 with boron trichloride in dichloromethane, followed by addition of methanol
Summary
Peptide-based imaging agents in nuclear medicine have tremendous utility in diagnosis, prognosis, and selection of therapeutic regimes for patients. The somatostatin receptor 2targeted imaging agent, 68Ga-DOTATATE for neuroendocrine tumors,[1−3] and more recently, the prostate specific membrane antigen targeted conjugate, 68Ga-HBED-PSMA,[4,5] have demonstrated clinical utility in patient prognosis and management. Other chelator systems have exhibited efficient 68Ga3+ radiolabeling properties, and the resulting radiolabeled conjugates are effective at delineating target tissue in vivo.[6−12] Among these are the tripodal tris(hydroxypyridinone) chelators containing three 1,6-dimethyl-3-hydroxypyridin-4-one groups that can coordinate radiometallic Ga3+ and Zr4+ ions,[13−15] as well as Fe3+ and Al3+ with high affinity.[16,17] Upon deprotonation of hydroxyl groups, the hexadentate O6 ligand, THP-Ac, can coordinate 68Ga3+ at mild pH (pH 6.5−7.5) and low ligand concentrations (10 μM) in
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