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Title: Isothiocyanate-functionalized bifunctional chelates and fac-[MI(CO)3]+ (M = Re, 99mTc) complexes for targeting uPAR in prostate cancer

item KASTEN, BENJAMIN - Washington State University
item MA, XIAOWEI - The Fourth Military Medical University
item CHENG, KAI - Stanford University
item BU, LIHONG - Stanford University
item SLOCUMB, WINSTON - Washington State University
item HAYES, THOMAS - Washington State University
item Trabue, Steven - Steve
item CHENG, ZHEN - The Fourth Military Medical University
item BENNY, PAUL - Washington State University

Submitted to: Bioconjugate Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/24/2015
Publication Date: 12/30/2015
Publication URL:
Citation: Kasten, B.B., Ma, X., Cheng, K., Bu, L., Slocumb, W.S., Hayes, T.R., Trabue, S.L., Cheng, Z., Benny, P.D. 2015. Isothiocyanate-functionalized bifunctional chelates and fac-[MI(CO)3]+ (M = Re, 99mTc) complexes for targeting uPAR in prostate cancer. Inorganic Chemistry. 27:130-142.

Interpretive Summary: Chemical compounds can be made with the ability to interact with cancer cells for identifying cancer that does not have to be invasive (requiring surgery). Locating cancer without surgery is a powerful tool for medical researchers. In this report, strategies for targeting prostate cancer cells is discussed and the synthesis of molecules that bind to cancer cells are reported. The molecules had a high affinity for prostate cancer. The results of this study show that targeting cancer cells with a molecule is possible and one was developed that successfully targeting targeted certain regions of the cancer cells. Information in this report will be of value for medical researchers and other scientists investigating imaging technology.

Technical Abstract: Developing strategies to rapidly incorporate the fac-[MI(CO)3]+ (M = Re, 99mTc) core into biological targeting vectors is a growing realm in radiopharmaceutical development. This work presents the preparation of a novel isothiocyanate-functionalized bifunctional chelate based on 2,2´-dipicolylamine (DPA) for labeling with fac-[MI(CO)3]+ and its application with a targeting peptide for imaging prostate cancer (CaP). The ligand and fac-[MI(CO)3]+ complexes were conjugated with a protected lysine analog (BocLys) as a model for reactions with biological targeting vectors containing amine functionalities. The intended products were obtained in moderate to excellent yields (30-95%) through both click, then chelate (ligand conjugation with BocLys followed by complexation with fac-[MI(CO)3]+) and chelate, then click (ligand complexation with fac-[MI(CO)3]+ followed by conjugation with BocLys) approaches as verified by full chemical analysis of the rhenium analogs and radio-HPLC comparison with the 99mTc analogs. The bifunctional chelate was then reacted with a peptide (AE105) that targets the urokinase-type plasminogen activator receptor (uPAR), an emerging biomarker in CaP prognosis. In vitro PC-3 cell uptake assays with the 99mTc-labeled peptide (8a) showed 4.2 ± 0.5% of the applied activity was taken up by the cells at 4 h, while this uptake was inhibited (1.5 ± 0.8%) by unlabeled AE105. In vivo biodistribution of 8a in murine models bearing PC-3 tumor xenografts led to favorable tumor uptake (3.7 ± 0.7% ID/g) at 4 h p.i. with low accumulation (<2% ID/g) in normal organs except those associated with peptide excretion (liver, intestines, kidneys). These results show that the isothiocyanate-functionalized ligand developed here successfully generates biologically active targeting vectors labeled with the fac-[MI(CO)3]+ through amine functionalization.