Tissue-targeting lead generation and optimization from random and directed screening of technetium-99m labeled tripeptide complex libraries in vivo.
BACKGROUND
Screening libraries against a molecular target in vitro are idealized models that cannot reflect the real state in vivo where biomolecules coexist and interact. C-terminal amide tripeptides labelled with Technetium-99m can provide a unique noninvasive approach to trace a large number of compounds in vivo.


METHODS
The C-terminal amide tripeptide libraries were synthesized on Rink Amide-MBHA resin using iterative and pooling protocol. Technetium (V) oxo core [TcO(3+)] was bound to each tripeptide via 4 deprotonated nitrogen atoms to form a library of 8000 (99m)Tc tripeptoid complexes. The radiocombinatorial screening (RCS) in vivo was carried out on SD rats and A549 tumour bearing mice.


RESULTS
Signals of tissue distribution and metabolism of libraries were recorded by counting or imaging and tissue targeting leads identified by both random and directed RCS. Among them, (99m)Tc RPA, (99m)Tc VIG and (99m)Tc RES had specific tissue targeting in kidney, liver and tumour respectively. The percent injected dose per gram tissue of (99m)Tc labelled leads in their target tissue was highly structure dependent. Because the nontarget tissue binding and the metabolism of (99m)Tc tripeptoid sublibraries were simultaneously monitored successfully by RCS, the interference of background activity was limited to the lowest level. Optimization of renal function agent from the labelled libraries was carried out by directed screening. (99m)Tc DSG was finally identified the most promising agent for renal function studies.


CONCLUSIONS
RCS in vivo is a powerful tool for the discovery of tissue targeting drugs. The potential screening bias is probably the major limitation of labelled libraries.
Zeng
Jun
J
Department of Nuclear Medicine, Shanghai Chest Hospital, Shanghai Jiao-Tong University, 241 Hui-hai Road, Shanghai 200030, China. jzeng2002@sohu.com
Liu
Ci-yi
CY
Xie
Wen-hui
WH
Hu
Si-long
SL
Jin
Mu-xiu
MX
D000818:Animals; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D005260:Female; D007553:Isotope Labeling; D007677:Kidney Function Tests; D008099:Liver / Q000000981:diagnostic imaging; D051379:Mice; D016513:Mice, SCID; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging; D019151:Peptide Library; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013667:Technetium; D014018:Tissue Distribution
D019151:Peptide Library; D019275:Radiopharmaceuticals; D013667:Technetium