Phenoxide-Bridged Zinc(II)-Bis(dipicolylamine) Probes for Molecular Imaging of Cell Death.
Cell death is involved in many pathological conditions, and there is a need for clinical and preclinical imaging agents that can target and report cell death. One of the best known biomarkers of cell death is exposure of the anionic phospholipid phosphatidylserine (PS) on the surface of dead and dying cells. Synthetic zinc(II)-bis(dipicolylamine) (Zn2BDPA) coordination complexes are known to selectively recognize PS-rich membranes and act as cell death molecular imaging agents. However, there is a need to improve in vivo imaging performance by selectively increasing target affinity and decreasing off-target accumulation. This present study compared the cell death targeting ability of two new deep-red fluorescent probes containing phenoxide-bridged Zn2BDPA complexes. One probe was a bivalent version of the other and associated more strongly with PS-rich liposome membranes. However, the bivalent probe exhibited self-quenching on the membrane surface, so the monovalent version produced brighter micrographs of dead and dying cells in cell culture and also better fluorescence imaging contrast in two living animal models of cell death (rat implanted tumor with necrotic core and mouse thymus atrophy). An (111)In-labeled radiotracer version of the monovalent probe also exhibited selective cell death targeting ability in the mouse thymus atrophy model, with relatively high amounts detected in dead and dying tissue and low off-target accumulation in nonclearance organs. The in vivo biodistribution profile is the most favorable yet reported for a Zn2BDPA complex; thus, the monovalent phenoxide-bridged Zn2BDPA scaffold is a promising candidate for further development as a cell death imaging agent in living subjects.
Department of Chemistry and Biochemistry, University of Notre Dame , 236 Nieuwland Science Hall, Notre Dame, Indiana 46556, United States.
Kasey J
KJ
Clear
Department of Chemistry and Biochemistry, University of Notre Dame , 236 Nieuwland Science Hall, Notre Dame, Indiana 46556, United States.
Kara M
KM
Harmatys
Department of Chemistry and Biochemistry, University of Notre Dame , 236 Nieuwland Science Hall, Notre Dame, Indiana 46556, United States.
Douglas R
DR
Rice
Freimann Life Science Center, University of Notre Dame , 400 Galvin Life Science, Notre Dame, Indiana 46556, United States.
William R
WR
Wolter
Freimann Life Science Center, University of Notre Dame , 400 Galvin Life Science, Notre Dame, Indiana 46556, United States.
Mark A
MA
Suckow
Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School , Worcester, Massachusetts 01655, United States.
Yuzhen
Y
Wang
Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School , Worcester, Massachusetts 01655, United States.
Mary
M
Rusckowski
Department of Chemistry and Biochemistry, University of Notre Dame , 236 Nieuwland Science Hall, Notre Dame, Indiana 46556, United States.
Bradley D
BD
Smith
D000818:Animals; D001284:Atrophy / Q000175:diagnosis / Q000473:pathology; D016466:CHO Cells; D016923:Cell Death; D045744:Cell Line, Tumor; D003412:Cricetulus; D005260:Female; D005456:Fluorescent Dyes / Q000737:chemistry*; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence / Q000379:methods; D057054:Molecular Imaging / Q000379:methods*; D009369:Neoplasms / Q000175:diagnosis / Q000473:pathology*; D061848:Optical Imaging / Q000379:methods; D009942:Organometallic Compounds / Q000737:chemistry*; D010718:Phosphatidylserines / Q000032:analysis; D010848:Picolinic Acids / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013950:Thymus Gland / Q000166:cytology / Q000473:pathology*
D005456:Fluorescent Dyes; D009942:Organometallic Compounds; D010718:Phosphatidylserines; D010848:Picolinic Acids; C529174:bis-dipicolylamine-Zinc(II)