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The use of copper radioisotopes in cancer diagnosis and radionuclide therapy is possible using chelators that are capable of binding CuII with sufficient stability in vivo to provide high tumour-to-background contrast. Here we report the design and synthesis of a new bifunctional chelator, 5-(8-methyl- 3,6,10,13,16,19-hexaaza-bicyclo[6.6.6]icosan-1-ylamino)-5-oxopentanoic acid (MeCOSar), that forms copper complexes of exceptional stability by virtue of a cage amine (sarcophagine) ligand and a new conjugate referred to as SarTATE, obtained by the conjugation of MeCOSar to the tumour-targeting peptide Tyr3-octreotate. Radiolabeling of SarTATE with 6CuII, a radioisotope suitable for positron emission tomography (PET), was fast (∼20 min), easily performed at room temperature and consistently resulted in high radiochemical purity (>99%). In vitro and in vivo evaluation of 64CuSarTATE demonstrated its high selectivity for tumour cells expressing somatostatin receptor 2 (sstr2). Biodistribution and PET imaging comparisons were made between 64CuSarTATE and 64Cu-labeled DOTA-Tyr3-octreotate (64CuDOTATATE). Both radiopharmaceuticals showed excellent uptake in sstr2-positive tumours at 2 h post-injection. While tumour uptake of 64CuDOTATATE decreased significantly at 24 h, 64CuSarTATE activity was retained, improving contrast at later time points. 64CuSarTATE accumulated less than 64CuDOTATATE in the nontarget organs, liver and lungs. The uptake of 64CuSarTATE in the kidneys was high at 2 h but showed significant clearance by 24 h. The new chemistry and pre-clinical evaluation presented here demonstrates that MeCOSar is a promising bifunctional chelator for Tyr3-octreotate that could be applied to a combined imaging and therapeutic regimen using a combination of 64Cu- and 67CuSarTATE complexes, owing to improved tumour-to-non-target organ ratios compared to 64CuDOTATATE at longer time points. [ABSTRACT FROM AUTHOR]

A new sarcophagine cage amine ligand with a pendent carboxylate functional group has been synthesised; the ligand has been conjugated to tumour targeting peptides ([Tyr3]-octreotate and [Lys3]-bombesin) and the conjugates radiolabelled with copper-64. [ABSTRACT FROM AUTHOR]

The synthesis and characterization of a silver complex of the tripodal triazole ligand, tris(benzyltriazolylmethyl)amine (TBTA, L¹), that is used as promoter to enhance CuI-catalyzed azide-alkyne cycloaddition (CuAAC) reactions is reported. X-ray analysis of the silver(I) complex with L¹ reveals a dinuclear cation, [Ag2(L¹)2]2+, that is essentially isostructural to the copper(I) analogue. While the [Ag2(L¹)2](BF4)2 complex provides catalysis for the azide-alkyne cycloaddition process, evidence is presented that this arises from trace copper contamination. The synthesis of silver(I), copper(II), and copper(I) complexes of a second tripodal ligand, tris(2-benzimidazolymethyl)amine (L²), which is used to enhance the rate of CuAAC reactions, is also reported. X-ray crystallography of the CuI complex [Cu3I(L²)2(CH3CN)2](BF4)3 offers structural insight into previous mechanistic speculation about the role of this ligand in the CuAAC reaction. [ABSTRACT FROM AUTHOR]

The synthesis of new cage amine macrobicyclic ligands with pendent carboxylate functional groups designed for application in copper radiopharmaceuticals is described. Reaction of [Cu((NH2)2sar)]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((NH2)2sar)]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 CuII 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 Lys3-bombesin. The synthesis of the first dimeric sarcophagine-peptide conjugate, possessing two Lys3-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 CuII from the conjugate even after two days of incubation in human serum. [ABSTRACT FROM AUTHOR]