title: 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.forename: Benjamin B
authors.initials: BB
authors.lastname: Kasten
authors.affiliation: Department of Nuclear Medicine, Xijing Hospital, Fourth Military Medical University , Xi'an, Shaanxi 710032, China.|Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Bio-X Program and Canary Center at Stanford for Cancer Early Detection, Stanford University , Stanford, California 94305, United States.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Ma
authors.affiliation: Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Bio-X Program and Canary Center at Stanford for Cancer Early Detection, Stanford University , Stanford, California 94305, United States.
authors.forename: Kai
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Bio-X Program and Canary Center at Stanford for Cancer Early Detection, Stanford University , Stanford, California 94305, United States.
authors.forename: Lihong
authors.initials: L
authors.lastname: Bu
authors.forename: Winston S
authors.initials: WS
authors.lastname: Slocumb
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hayes
authors.affiliation: United States Department of Agriculture, National Soil Tilth Laboratory , Ames, Iowa 50011, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Trabue
authors.affiliation: Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Bio-X Program and Canary Center at Stanford for Cancer Early Detection, Stanford University , Stanford, California 94305, United States.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cheng
authors.forename: Paul D
authors.initials: PD
authors.lastname: Benny
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods; D015609:Organotechnetium Compounds / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000493:pharmacokinetics*; D055293:Receptors, Urokinase Plasminogen Activator / Q000378:metabolism*; D012211:Rhenium / Q000737:chemistry; D013667:Technetium / Q000737:chemistry; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D002614:Chelating Agents; D015609:Organotechnetium Compounds; D010455:Peptides; D019275:Radiopharmaceuticals; D055293:Receptors, Urokinase Plasminogen Activator; D012211:Rhenium; D013667:Technetium