Isothiocyanate-Functionalized Bifunctional Chelates and fac-[M(I)(CO)3](+) (M = Re, (99m)Tc) Complexes for Targeting uPAR in Prostate Cancer.

Abstract

Developing new strategies to rapidly incorporate the fac-[M(I)(CO)3](+) (M = Re, (99m)Tc) core into biological targeting vectors in radiopharmaceuticals continues to expand as molecules become more complex and as efforts to minimize nonspecific binding increase. This work examines a novel isothiocyanate-functionalized bifunctional chelate based on 2,2'-dipicolylamine (DPA) specifically designed for complexing the fac-[M(I)(CO)3](+) core. Two strategies (postlabeling and prelabeling) were explored using the isothiocyanate-functionalized DPA to determine the effectiveness of assembly on the overall yield and purity of the complex with amine containing biomolecules. A model amino acid (lysine) examined (1) amine conjugation of isothiocyanate-functionalized DPA followed by complexation with fac-[M(I)(CO)3](+) (postlabeling) and (2) complexation of fac-[M(I)(CO)3](+) with isothiocyanate-functionalized DPA followed by amine conjugation (prelabeling). Conducted with stable Re and radioactive (99m)Tc analogs, both strategies formed the product in good to excellent yields under macroscopic and radiotracer concentrations. A synthetic peptide (AE105) which targets an emerging biomarker in CaP prognosis, urokinase-type plasminogen activator receptor (uPAR), was also explored using the isothiocyanate-functionalized DPA strategy. In vitro PC-3 (uPAR+) cell uptake assays with the (99m)Tc-labeled peptide (8a) showed 4.2 ± 0.5% uptake at 4 h. In a murine model bearing PC-3 tumor xenografts, in vivo biodistribution of 8a led to favorable tumor uptake (3.7 ± 0.7% ID/g) at 4 h p.i. with relatively low accumulation (<2% ID/g) in normal organs not associated with normal peptide excretion. These results illustrate the promise of the isothiocyanate-functionalized approach for labeling amine containing biological targeting vectors with fac-[M(I)(CO)3](+).

• Authors: Benjamin B Kasten, Xiaowei Ma, Kai Cheng, Lihong Bu, Winston S Slocumb, Thomas R Hayes, Steven Trabue, Zhen Cheng, Paul D Benny
• Journal: Bioconjugate chemistry (Bioconjug Chem) Vol. 27 Issue 1 Pg. 130-42 (Jan 20 2016) ISSN: 1520-4812 [Electronic] United States
• PMID: 26603218 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Chelating Agents
• Organotechnetium Compounds
• Peptides
• Radiopharmaceuticals
• Receptors, Urokinase Plasminogen Activator
• Rhenium
• Technetium

Topics

• Animals
• Cell Line, Tumor
• Chelating Agents (chemistry, pharmacology)
• Humans
• Male
• Mice, Nude
• Molecular Targeted Therapy (methods)
• Organotechnetium Compounds (chemistry)
• Peptides (chemistry)
• Prostatic Neoplasms (drug therapy)
• Radiopharmaceuticals (chemistry, pharmacokinetics)
• Receptors, Urokinase Plasminogen Activator (metabolism)
• Rhenium (chemistry)
• Technetium (chemistry)
• Tissue Distribution
• Xenograft Model Antitumor Assays