Iminodiacetic acid as bifunctional linker for dimerization of cyclic RGD peptides.
BACKGROUND
In this study, I2P-RGD2was used as the example to illustrate a novel approach for dimerization of cyclic RGD peptides. The main objective of this study was to explore the impact of bifunctional linkers (glutamic acid vs. iminodiacetic acid) on tumor-targeting capability and excretion kinetics of the99mTc-labeled dimeric cyclic RGD peptides.


METHODS
HYNIC-I2P-RGD2was prepared by reacting I2P-RGD2with HYNIC-OSu in the presence of diisopropylethylamine, and was evaluated for its αvβ3binding affinity against125I-echistatin bound to U87MG glioma cells.99mTc-I2P-RGD2was prepared with high specific activity (~185GBq/μmol). The athymic nude mice bearing U87MG glioma xenografts were used to evaluate its biodistribution properties and image quality in comparison with those of99mTc-3P-RGD2.


RESULTS
The IC50value for HYNIC-I2P-RGD2was determined to be 39±6nM, which was very close to that (IC50=33±5nM) of HYNIC-3P-RGD2. Replacing glutamic acid with iminodiacetic acid had little impact on αvβ3binding affinity of cyclic RGD peptides.99mTc-I2P-RGD2and99mTc-3P-RGD2shared similar tumor uptake values over the 2h period, and its αvβ3-specificity was demonstrated by a blocking experiment. The uptake of99mTc-I2P-RGD2was significantly lower than99mTc-3P-RGD2in the liver and kidneys. The U87MG glioma tumors were visualized by SPECT with excellent contrast using both99mTc-I2P-RGD2and99mTc-3P-RGD2.


CONCLUSIONS
Iminodiacetic acid is an excellent bifunctional linker for dimerization of cyclic RGD peptides. Bifunctional linkers have significant impact on the excretion kinetics of99mTc radiotracers. Because of its lower liver uptake and better tumor/liver ratios,99mTc-I2P-RGD2may have advantages over99mTc-3P-RGD2for diagnosis of tumors in chest region.
International Medicine Center, International Medicine Division, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Dong
D
Xu
Department of Nuclear Medicine, Fuwai Hospital, the National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Zuo-Quan
ZQ
Zhao
Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, China.
Shu-Ting
ST
Chen
International Medicine Center, International Medicine Division, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Department of Nuclear Medicine, Fuwai Hospital, the National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Yong
Y
Yang
Department of Nuclear Medicine, Fuwai Hospital, the National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: nuclearfw@126.com.
Wei
W
Fang
School of Health Sciences, Purdue University, West Lafayette, IN, USA. Electronic address: liu100@purdue.edu.
Shuang
S
Liu
D000818:Animals; D019281:Dimerization; D005260:Female; D007098:Imino Acids / Q000737:chemistry*; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D011854:Radiochemistry; D000072098:Single Photon Emission Computed Tomography Computed Tomography; D013379:Substrate Specificity; D013667:Technetium / Q000737:chemistry; D014018:Tissue Distribution
D007098:Imino Acids; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide; D013667:Technetium; C008109:iminodiacetic acid
(99m)Tc-labeling; Dimeric cyclic RGD peptides; Integrin α(v)β(3); SPECT; Tumor imaging