title: PET imaging of tumours with a 64Cu labeled macrobicyclic cage amine ligand tethered to Tyr3-octreotate.
abstract: 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.
authors.affiliation: School of Chemistry, The University of Melbourne, Parkville, VIC, Australia. pauld@unimelb.edu.au.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Paterson
authors.forename: Peter
authors.initials: P
authors.lastname: Roselt
authors.forename: Delphine
authors.initials: D
authors.lastname: Denoyer
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.forename: David
authors.initials: D
authors.lastname: Binns
authors.forename: Wayne
authors.initials: W
authors.lastname: Noonan
authors.forename: Charmaine M
authors.initials: CM
authors.lastname: Jeffery
authors.forename: Roger I
authors.initials: RI
authors.lastname: Price
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: White
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Hicks
authors.forename: Paul S
authors.initials: PS
authors.lastname: Donnelly
mesh_terms: D000588:Amines / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry*; D003301:Copper Radioisotopes / Q000737:chemistry; D018360:Crystallography, X-Ray; D007553:Isotope Labeling; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008968:Molecular Conformation; D009369:Neoplasms / Q000000981:diagnostic imaging; D010456:Peptides, Cyclic / Q000737:chemistry*; D049268:Positron-Emission Tomography; D011859:Radiography; D019275:Radiopharmaceuticals / Q000737:chemistry* / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000588:Amines; D056831:Coordination Complexes; D003301:Copper Radioisotopes; D008024:Ligands; D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; C470036:octreotate, Tyr(3)-