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PET imaging of tumours with a 64Cu labeled macrobicyclic cage amine ligand tethered to Tyr3-octreotate

Paterson,BM, Roselt,P, Denoyer,D, Cullinane,C, Binns,D, Noonan,W, Jeffery,CM, Price,RI, White,JM, Hicks,RJ and Donnelly,PS 2014, PET imaging of tumours with a 64Cu labeled macrobicyclic cage amine ligand tethered to Tyr3-octreotate, Dalton transactions, vol. 43, no. 3, pp. 1386-1396, doi: 10.1039/c3dt52647j.

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Title PET imaging of tumours with a 64Cu labeled macrobicyclic cage amine ligand tethered to Tyr3-octreotate
Author(s) Paterson,BM
Denoyer,DORCID iD for Denoyer,D
Journal name Dalton transactions
Volume number 43
Issue number 3
Start page 1386
End page 1396
Total pages 11
Publisher Royal Society of Chemistry
Place of publication Cambridge, Eng.
Publication date 2014-01-21
ISSN 1477-9226
Keyword(s) Amines
Cell Line, Tumor
Coordination Complexes
Copper Radioisotopes
Crystallography, X-Ray
Isotope Labeling
Mice, Inbred BALB C
Molecular Conformation
Peptides, Cyclic
Positron-Emission Tomography
Tissue Distribution
Summary 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.
Language eng
DOI 10.1039/c3dt52647j
Field of Research 111201 Cancer Cell Biology
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
ERA Research output type C Journal article
Copyright notice ©2014, Royal Society of Chemistry
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