title: Synthesis and evaluation of radioiodinated acyloxymethyl ketones as activity-based probes for cathepsin B.
abstract: 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 [(125)I]11a and 1.12% ± 0.08% ID/g for [(125)I]23a at 30 min. The tumor-to-blood ratios reached 1.2 for [(125)I]23a and 1.6 for [(125)I]11a after 23 h. The more hydrophilic [(125)I]23a showed an improved clearance profile with a superior tumor-to-muscle ratio of 7.0 compared to 3.4 for [(125)I]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.
authors.affiliation: Department of Chemistry & Chemical Biology, McMaster University , 1280 Main Street West, Hamilton, Ontario L8S 4M1, Canada.
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Edem
authors.forename: Shannon
authors.initials: S
authors.lastname: Czorny
authors.forename: John F
authors.initials: JF
authors.lastname: Valliant
mesh_terms: D000818:Animals; D001565:Benzoates / Q000737:chemistry; D043402:Cathepsin A / Q000737:chemistry; D002401:Cathepsin B / Q000737:chemistry*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007455:Iodine / Q000737:chemistry; D007457:Iodine Radioisotopes / Q000737:chemistry*; D007659:Ketones / Q000737:chemistry*; D007700:Kinetics; D008024:Ligands; D008099:Liver / Q000378:metabolism; D051379:Mice; D009132:Muscles / Q000187:drug effects; D009368:Neoplasm Transplantation; D013696:Temperature
chemical_list: D001565:Benzoates; D004791:Enzyme Inhibitors; D007457:Iodine Radioisotopes; D007659:Ketones; D008024:Ligands; D007455:Iodine; D043402:Cathepsin A; D002401:Cathepsin B