Evaluation of strained alkynes for Cu-free click reaction in live mice

Abstract Introduction We report on our evaluation of the strain-promoted cyclooctyne-azide cycloaddition reaction for use in tumor pretargeting, comprising a side-by-side comparison of probes 1 – 3 bearing three distinct cyclooctyne moieties based respectively on the 1st and 2nd generation difluorin...

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Published in:	Nuclear medicine and biology Vol. 40; no. 3; pp. 415 - 423
Main Authors:	van den Bosch, S.M, Rossin, R, Renart Verkerk, P, ten Hoeve, W, Janssen, H.M, Lub, J, Robillard, M.S
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-04-2013
Subjects:	Alkynes - chemistry Alkynes - metabolism Alkynes - pharmacokinetics Animals Antibodies Antibodies, Monoclonal, Murine-Derived - chemistry Antibodies, Monoclonal, Murine-Derived - therapeutic use Azide Azides - chemistry Bioorthogonal Click Chemistry Copper-free click Cyclooctyne Drug Stability Female Heterocyclic Compounds, 1-Ring - chemistry Lutetium - therapeutic use Mice Pretargeting Radioisotopes - therapeutic use Radiology Rituximab Bioorthogonal Antibodies Azide Copper-free click Pretargeting Cyclooctyne
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Summary:	Abstract Introduction We report on our evaluation of the strain-promoted cyclooctyne-azide cycloaddition reaction for use in tumor pretargeting, comprising a side-by-side comparison of probes 1 – 3 bearing three distinct cyclooctyne moieties based respectively on the 1st and 2nd generation difluorinated cyclooctyne and the 1st generation dibenzocyclooctyne. Methods The probes were synthesized and labeled with177 Lu with high yields. The probe stability and reactivity towards azides were evaluated in PBS and mouse serum, and their blood clearance, biodistribution and in vivo reactivity were evaluated in tumor-free mice. Results In serum the three probes exhibited sufficient stability for a pretargeting application with half-lives of 12–19 h. In PBS, probes 2 and 3 were more reactive towards azido-conjugated Rituximab (Rtx-N3 ) than 1 , but in contrast to 1 , their reactivity decreased in mouse serum and mouse serum albumin solutions, as a result of covalent and non-covalent interactions with albumin. Biodistribution data confirmed the interactions with serum proteins in circulation:177 Lu- 1 showed a fast elimination from blood (t1/2,β = 0.31 h), while177 Lu- 2 and177 Lu- 3 were retained in blood for longer periods of time (t1/2,β = 1.08 and 3.58 h, respectively). Dual isotope biodistribution experiments assessing the reaction between125 I-Rtx-N3 and177 Lu- 1 – 3 in circulation in mice showed a very limited retention of 2 and 3 in blood rich organs, indicating a minimal reactivity, while no such retention was observed for 1. Conclusion The low reactivity of the studied cyclooctynes, and their serum interactions preclude their use at the low in vivo concentrations typical for pretargeting applications.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0969-8051 1872-9614
DOI:	10.1016/j.nucmedbio.2012.12.006