Synthesis and Evaluation of New Generation Cross-Bridged Bifunctional Chelator for (64)Cu Radiotracers.
Bifunctional chelators have been successfully used to construct (64)Cu-labeled radiopharmaceuticals. Previously reported chelators with cross-bridged cyclam backbones have various essential features such as high stability of the copper(II) complex, high efficiency of radiolabeling at room temperature, and good biological inertness of the radiolabeled complex, along with rapid body clearance. Here, we report a new generation propylene-cross-bridged chelator with hybrid acetate/phosphonate pendant groups (PCB-TE1A1P) developed with the aim of combining these key properties in a single chelator. The PCB-TE1A1P was synthesized from cyclam with good overall yield. The Cu(II) complex of our chelator showed good robustness in kinetic stability evaluation experiments, such as acidic decomplexation and cyclic voltammetry studies. The Cu(II) complex of PCB-TE1A1P remained intact under highly acidic conditions (12 M HCl, 90 °C) for 8 d and showed quasi-reversible reduction/oxidation peaks at -0.77 V in electrochemical studies. PCB-TE1A1P was successfully radiolabeled with (64)Cu ions in an acetate buffer at 60 °C within 60 min. The electrophoresis study revealed that the (64)Cu-PCB-TE1A1P complex has net negative charge in aqueous solution. The biodistribution and in vivo stability study profiles of (64)Cu-PCB-TE1A1P indicated that the radioactive complex was stable under physiological conditions and cleared rapidly from the body. A whole body positron emission tomography (PET) imaging study further confirmed high in vivo stability and fast clearance of the complex in mouse models. In conclusion, PCB-TE1A1P has good potential as a bifunctional chelator for (64)Cu-based radiopharmaceuticals, especially those involving peptides.
Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University , Daegu 700-422, South Korea.
Ajit V
AV
Dale
Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences , Seoul 139-706, South Korea.
Gwang Il
GI
An
Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University , Daegu 700-422, South Korea.
Darpan N
DN
Pandya
Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University , Daegu 700-422, South Korea.
Yeong Su
YS
Ha
Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University , Daegu 700-422, South Korea.
Nikunj
N
Bhatt
Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University , Daegu 700-422, South Korea.
Nisarg
N
Soni
Department of Energy Systems Engineering, Daegu Gyeongbuk Institute of Science & Technology , Daegu 711-873, South Korea.
Hochun
H
Lee
Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University , Daegu 700-422, South Korea.
Heesu
H
Ahn
Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University , Daegu 700-422, South Korea.
Swarbhanu
S
Sarkar
Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University , Daegu 700-422, South Korea.
Woonghee
W
Lee
Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University , Daegu 700-422, South Korea.
Phuong Tu
PT
Huynh
Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences , Seoul 139-706, South Korea.
Jung Young
JY
Kim
Department of Biomedical Science and Clinical Trial Center, BK21 PLUS, KNU Bio-Medical Convergence Program, Kyungpook National University Graduate School and Hospital , Daegu 700-422, South Korea.
Mi-Ri
MR
Gwon
Analysis Research Division, Daegu Center, Korea Basic Science Institute , Daegu 702-701, South Korea.
Sung Hong
SH
Kim
Pohang Center for Evaluation of Biomaterials, Pohang Technopark Foundation , Gyeongbuk 790-834, South Korea.
Jae Gyu
JG
Park
Department of Biomedical Science and Clinical Trial Center, BK21 PLUS, KNU Bio-Medical Convergence Program, Kyungpook National University Graduate School and Hospital , Daegu 700-422, South Korea.
Young-Ran
YR
Yoon
Department of Molecular Medicine, BK21 Plus KNU Biomedical Convergence Program, Kyungpook National University , Daegu 700-422, South Korea.
Jeongsoo
J
Yoo
D000818:Animals; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry*; D003301:Copper Radioisotopes / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D002614:Chelating Agents; D003301:Copper Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals