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Synthesis and Evaluation of Radioiodinated Acyloxymethyl Ketones as Activity-Based Probes for Cathepsin B

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journal contribution
posted on 26.11.2014, 00:00 by Patricia E. Edem, Shannon Czorny, John F. Valliant
Dipeptidyl (acyloxy)­methyl ketones (AOMKs) were functionalized with different iodine-containing prosthetic groups to generate a library of candidate cathepsin B probes. Compound 23a, (S)-20-[(S)-2-{[(benzyloxy)­carbonyl]­amino}-3-phenylpropanamido]-1-(4-iodophenyl)-1,14,21-trioxo-5,8,11-trioxa-2,15-diazadocosan-22-yl 2,4,6-trimethylbenzoate, was identified as a potential lead through in vitro screening, having a Ki = 181 ± 9 nM and demonstrating the ability to effectively label active cathepsin B in vitro. Its less potent analogue 11a, (S)-3-[(S)-2-{[(benzyloxy)­carbonyl]­amino}-3-phenylpropanamido]-7-[6-(4-iodobenzamido)­hexanamido]-2-oxoheptyl 2,4,6-trimethylbenzoate, was also tested as a comparison. Biodistribution studies of the iodine-125-labeled compounds in MDA-MB-231 mouse xenografts exhibited tumor uptake of 0.58% ± 0.06% injected dose per gram (ID/g) for [125I]11a and 1.12% ± 0.08% ID/g for [125I]23a at 30 min. The tumor-to-blood ratios reached 1.2 for [125I]23a and 1.6 for [125I]11a after 23 h. The more hydrophilic [125I]23a showed an improved clearance profile with a superior tumor-to-muscle ratio of 7.0 compared to 3.4 for [125I]11a at 23 h. Iodinated AOMK ligands are suitable in vitro probes for cathepsin B and hold promise as a platform to develop molecular imaging probes.