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 ^99mTc 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, ^99mTc RPA, ^99mTc VIG and ^99mTC RES had specific tissue targeting in kidney, liver and tumour respectively. The percent injected dose per gram tissue of ^99mTc labelled leads in their target tissue was highly structure dependent. Because the nontarget tissue binding and the metabolism of ^99mTc 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. ^99mTc 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.

Integrated identification method of rheological model of sandstone in Sanmenxia bauxite

Based on the uniaxial compression creep experiments conducted on bauxite sandstone obtained from Sanmenxia,typical creep experiment curves were obtained.From the characteristics of strain component of creep curves,the creep strain is composed of instantaneous elastic strain,ε（me）,instantaneous plastic strain,ε（mp）,viscoelastic strain,ε（ce）,and viscoplastic strain,ε（cp）.Based on the characteristics of instantaneous plastic strain,a new element of instantaneous plastic rheology was introduced,instantaneous plastic modulus was defined,and the modified Burgers model was established.Then identification of direct screening method in this model was completed.According to the mechanical properties of rheological elements,one- and three-dimensional creep equations in different stress levels were obtained.One-dimensional model parameters were identified by the method of least squares,and in the process of computation,Gauss-Newton iteration method was applied.Finally,by fitting the experimental curves,the correctness of direct method model was verified,then the examination of posterior exclusive method of the model was accomplished.The results showed that in the improved Burgers models,the rheological characteristics of sandstone are embodied properly,microscopic analysis of creep curves is also achieved,and the correctness of comprehensive identification method of rheological model is verified.