PET imaging of tumours with a 64 Cu labeled macrobicyclic cage amine ligand tethered to Tyr 3 -octreotate

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Abstract
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 64CuII, 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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