PET imaging of tumours with a 64Cu labeled macrobicyclic cage amine ligand tethered to Tyr3-octreotateElectronic supplementary information (ESI) available: 1H and 13C NMR spectra, HPLC traces, X-ray crystal data and biodistribution data. CCDC 915824. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3dt52647j

• Main Authors: Paterson, Brett M, Roselt, Peter, Denoyer, Delphine, Cullinane, Carleen, Binns, David, Noonan, Wayne, Jeffery, Charmaine M, Price, Roger I, White, Jonathan M, Hicks, Rodney J, Donnelly, Paul S
• Format: Article
• Language: English
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/c3dt52647j

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 Tyr 3 -octreotate. Radiolabeling of SarTATE with 64 Cu 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 64 CuSarTATE demonstrated its high selectivity for tumour cells expressing somatostatin receptor 2 (sstr2). Biodistribution and PET imaging comparisons were made between 64 CuSarTATE and 64 Cu-labeled DOTA-Tyr 3 -octreotate ( 64 CuDOTATATE). Both radiopharmaceuticals showed excellent uptake in sstr2-positive tumours at 2 h post-injection. While tumour uptake of 64 CuDOTATATE decreased significantly at 24 h, 64 CuSarTATE activity was retained, improving contrast at later time points. 64 CuSarTATE accumulated less than 64 CuDOTATATE in the non-target organs, liver and lungs. The uptake of 64 CuSarTATE 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 Tyr 3 -octreotate that could be applied to a combined imaging and therapeutic regimen using a combination of 64 Cu- and 67 CuSarTATE complexes, owing to improved tumour-to-non-target organ ratios compared to 64 CuDOTATATE at longer time points. A new 64 Cu bifunctional chelator conjugated to Tyr 3 -octreotate permits PET imaging 24 hours post-injection with high levels of selective tumour uptake.