School of Chemistry - Research Publications

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Author: White, Jonathan × Author: SCANLON, DENIS × Type: Journal Article × Start date: 2011 × End date: 2011 ×

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    Gallium-68 Complex of a Macrobicyclic Cage Amine Chelator Tethered to Two Integrin-Targeting Peptides for Diagnostic Tumor Imaging
    Ma, MT ; Neels, OC ; Denoyer, D ; Roselt, P ; Karas, JA ; Scanlon, DB ; White, JM ; Hicks, RJ ; Donnelly, PS (AMER CHEMICAL SOC, 2011-10)
    Tumor-targeting peptides radiolabeled with positron-emitting (68)Ga are promising candidates as new noninvasive diagnostic agents for positron emission tomography (PET). The targeting peptides are tethered to a chelator that forms a stable coordination complex with Ga(3+) that is inert to dissociation of Ga(3+)in vivo. Metal complexes of macrobicyclic hexaamine "sarcophagine" (sar = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane) ligands exhibit remarkable stability as a result of the encapsulating nature of the cage amine ligand. A Ga(3+) sarcophagine complex, [Ga-(1-NH(3)-8-NH(2)-sar)](4+), has been characterized using X-ray crystallography, demonstrating that Ga(3+) is coordinated to six nitrogen atoms in a distorted octahedral complex. A bifunctional derivative of (NH(2))(2)sar, possessing two aliphatic linkers with carboxylic acid functional groups has been attached to two cyclic-RGD peptides that target the α(v)β(3) integrin receptor that is overexpressed in some types of tumor tissue. This dimeric species can be radiolabeled with (68)Ga(3+) in >98% radiochemical yield and (68)Ga(3+) does not dissociate from the ligand in the presence of transferrin, an endogenous protein with high affinity for Ga(3+). Biodistribution and micro-PET imaging studies in tumor-bearing mice indicate that the tracer accumulates specifically in tumors with high integrin expression. The high tumor uptake is coupled with low nonspecific uptake and clearance predominantly through the kidneys resulting in high-quality PET images in animal models.
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    Macrobicyclic Cage Amine Ligands for Copper Radiopharmaceuticals: A Single Bivalent Cage Amine Containing Two Lys3-bombesin Targeting Peptides
    Ma, MT ; Cooper, MS ; Paul, RL ; Shaw, KP ; Karas, JA ; Scanlon, D ; White, JM ; Blower, PJ ; Donnelly, PS (AMER CHEMICAL SOC, 2011-07-18)
    The synthesis of new cage amine macrobicyclic ligands with pendent carboxylate functional groups designed for application in copper radiopharmaceuticals is described. Reaction of [Cu((NH(2))(2)sar)](2+) (sar = 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane) with either succinic or glutaric anhydride results in selective acylation of the primary amine atoms of [Cu((NH(2))(2)sar)](2+) to give derivatives with either one or two aliphatic carboxylate functional groups separated from the cage amine framework by either a four- or five-atom linker. The Cu(II) serves to protect the secondary amine nitrogen atoms from acylation, and can be removed to give the free ligands. The newly appended carboxylate functional groups can be used as sites of attachment for cancer-targeting peptides such as Lys(3)-bombesin. The synthesis of the first dimeric sarcophagine-peptide conjugate, possessing two Lys(3)-bombesin peptides tethered to a single cage amine, is presented. This species has been radiolabeled with copper-64 at ambient temperature and there is minimal dissociation of Cu(II) from the conjugate even after two days of incubation in human serum.