RGD conjugates of the H2 dedpa scaffold: synthesis, labeling and imaging with68 Ga

Abstract Introduction The rekindled interest in the68 Ga generator as an attractive positron emission tomography generator system has led us and others to investigate novel chelate systems for68 Ga. We have previously reported our findings with the acyclic, rapidly coordinating chelate H2 dedpa and...

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Published in:Nuclear medicine and biology 2012, Vol.39 (6), p.785-794
Main Authors: Boros, Eszter, Ferreira, Cara L, Yapp, Donald T.T, Gill, Rajanvir K, Price, Eric W, Adam, Michael J, Orvig, Chris
Format: Article
Language:English
Subjects:
Radiology
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Summary:Abstract Introduction The rekindled interest in the68 Ga generator as an attractive positron emission tomography generator system has led us and others to investigate novel chelate systems for68 Ga. We have previously reported our findings with the acyclic, rapidly coordinating chelate H2 dedpa and its model derivatives. Methods In this report, we describe the synthesis of the corresponding bifunctional chelate scaffolds (H2 dp-bb-NCS and H2 dp-N-NCS ) as well as the radiolabeling properties, transferrin stability, binding to the target using in vitro cell models and in vivo behavior the corresponding conjugates with the αv β3 targeting cyclic pentapeptide cRGDyK (monomeric H2 RGD-1 and dimeric H2 RGD-2 ). Results The ability of the conjugated ligands to coordinate Ga isotopes within 10 min at room temperature at concentrations of 1 nmol was confirmed. Complex [67 Ga( RGD-1 )]+ was more stable (92% after 2 h) than [67 Ga( RGD-2 )]+ (73% after 2 h) in a transferrin challenge experiment. IC50 values for both conjugates (H2 RGD-1 and H2 RGD-2 ) and nonconjugated RGD were determined in a cell-based competitive binding assay with125 I-echistatin using U87MG cells, where enhanced specific binding was observed for the multivalent H2 RGD-2 conjugate compared to the monovalent H2 RGD-1 and nonconjugated cRGDyK. The U87MG cell line was also used to generate subcutaneous xenograft tumors on RAG2M mice, which were used to evaluate the in vivo properties of [68 Ga( RGD-1 )]+ and [68 Ga( RGD-2 )]+ . After 2 h of dynamic imaging, both block and nonblock mice were sacrificed to collect select organs at the 2-h time point. Although the uptake is specific, as judged from the ratios of nonblock to block (2.36 with [67 Ga( RGD-1 )]+ , 1.46 with [67 Ga( RGD-2 )]+ ), both conjugates display high uptake in blood. Conclusions We have successfully synthesized and applied the first bifunctional versions of H2 dedpa for conjugation to a targeting vector and subsequent imaging of the corresponding conjugates.
ISSN:0969-8051
1872-9614
DOI:10.1016/j.nucmedbio.2012.01.003