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.
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Authors | Brett M Paterson, Peter Roselt, Delphine Denoyer, Carleen Cullinane, David Binns, Wayne Noonan, Charmaine M Jeffery, Roger I Price, Jonathan M White, Rodney J Hicks, Paul S Donnelly |
Journal | Dalton transactions (Cambridge, England : 2003)
(Dalton Trans)
Vol. 43
Issue 3
Pg. 1386-96
(Jan 21 2014)
ISSN: 1477-9234 [Electronic] England |
PMID | 24202174
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Amines
- Coordination Complexes
- Copper Radioisotopes
- Ligands
- Peptides, Cyclic
- Radiopharmaceuticals
- octreotate, Tyr(3)-
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Topics |
- Amines
(chemistry)
- Animals
- Cell Line, Tumor
- Coordination Complexes
(chemical synthesis, chemistry)
- Copper Radioisotopes
(chemistry)
- Crystallography, X-Ray
- Isotope Labeling
- Ligands
- Mice
- Mice, Inbred BALB C
- Molecular Conformation
- Neoplasms
(diagnostic imaging)
- Peptides, Cyclic
(chemistry)
- Positron-Emission Tomography
- Radiography
- Radiopharmaceuticals
(chemistry, metabolism)
- Tissue Distribution
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