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

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. and in mice with induced rheumatoid arthritis. PET imaging with [68Ga(HP3-RGD3)] enables clear delineation of v3integrin receptor expression in vivo. == Introduction == Peptide-based imaging agents in nuclear medicine have Rabbit Polyclonal to POLR1C tremendous utility in diagnosis, prognosis, and selection of therapeutic regimes for patients. Radiometals can be incorporated into clinically relevant peptides via a bifunctional chelator, providing effective and sensitive radiotracers that can be prepared conveniently in a radiopharmacy. The metallic isotope68Ga possesses decay properties that are suitable for positron emission tomography (PET) (68 min half-life, 1899 keV +emission with 88% abundance), and the availability of a pharmaceutical grade68Ge/68Ga generator means that the number of molecular imaging agents based on68Ga is likely to increase in the coming years. The somatostatin receptor 2-targeted imaging agent, 68Ga-DOTATATE for neuroendocrine tumors, 13and more recently, the prostate specific membrane antigen targeted conjugate, 68Ga-HBED-PSMA, 4, 5have demonstrated clinical utility in patient prognosis and management. Other chelator systems have exhibited efficient68Ga3+radiolabeling properties, and the resulting radiolabeled conjugates are effective at delineating target tissue in vivo. 612Among 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, 1315as well as Fe3+and Al3+with high affinity. 16, 17Upon deprotonation of hydroxyl groups, the hexadentate O6ligand, THP-Ac, can coordinate68Ga3+at mild pH (pH 6. 57. 5) and low ligand concentrations (10 M) in <5 min. 13Bifunctional derivatives of THP-Ac can be attached to peptides, with the resulting conjugates able to rapidly and quantitatively coordinate aqueous68Ga3+at room temperature at pH 57. 18, 19 Multimeric peptide-based imaging agents that incorporate more than one peptide targeting group (and in particular small peptides that target the v3integrin receptor) have demonstrated increased accumulation of activity at tissue targets in vivo relative to their monomeric analogues, and are effective contrast agents. 8, EC-17 12, 2027This increased accumulation of radiotracer in the case of multimeric compounds can be attributed to either (i) divalent binding, where two targeting peptides bind to two receptors simultaneously, requiring sufficient distance between the two intramolecular targeting ligands to form this bridge; or (ii) an increased local effective concentration of targeting peptide at the receptor site, resulting in a shift in equilibrium toward peptide receptor binding. In the case where the multimeric derivative has an increased persistence in the blood pool in vivo relative to the monomeric derivative, it is also possible that increased uptake is a result of increased bioavailability. Dendritic and multimeric chelator systems for coordination of Gd3+and lanthanides provide enhanced contrast as MRI agents compared to their single-chelator counterparts, EC-17 in large part due to the increased number of metal complexes present. 2836Multimeric constructs containing multiple chelating groups (including hydroxypyridinones) have also been synthesized for the purposes of sequestering trace metal ions. 17, 37A small body of work has been described in which the number of radiometal coordination sites on a radiolabeled protein/antibody has been increased by incorporation of either a dendrimer possessing multiple chelating groups, 3841or a pendant function (such as polylysine) on which multiple chelators are appended. 4244In these cases, the functionalized/radiolabeled biomolecule retained affinity for receptor targets in vitro40, 41, 44and in vivo. 38, 39, 42, 43Additionally, when compared to bioconjugates containing fewer chelating groups, dendrimer or multichelator conjugated proteins demonstrated higher specific activitythat EC-17 is, a higher number of radionuclides were bound per bioconjugate compared to homologues containing a single chelator. 38, 4143In some cases, this resulted in higher concentrations of radioactivity at target tissue (tumors) in vivo. 42 We are interested in using tris(hydroxypyridinone) ligands to explore new ways of increasing accumulated radioactivity at diseased tissue where target receptors are localized in vivo. Here we aim to incorporate multiple in vivo targeting peptide groups and multiple chelator groups into a single molecule, thus increasing the affinity of the radiolabeled conjugate for receptors in vivo as well as increasing the specific activity of the radiolabeled species itself. This approach mimics that of multifunctionalized nanoparticles, where multiple copies of a targeting biomolecule/modifying agent and multiple chelating groups.