The use of copper radioisotopes in cancer diagnosis and radionuclide therapy is possible using chelators that are capable of binding Cu^II 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 ⁶⁴Cu^II, 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 non-target 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.

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