The correlation of serum protein association and cellular uptake with lipophilicity and polarity of the backbone substituents of the technetium‐99m‐amine‐oxime chelates

Abstract

Detection of tumor hypoxia is of importance because hypoxic cancer cells can resist radiation therapy and also induce molecules to help them surviving and metastasizing. Our previous study has reported the development of technetium-99m labeled amine-oxime compounds containing 2-nitroimidazoles to target hypoxic cells. In order to develop new generation of 99m Tc, 64 Cu, and 67 Cu based amine-oxime chelates with improved selectivity on tumor hypoxia in the future, it is important to understand the correlation of some structural parameters such as lipophilicity and polarity of the backbone -constituents of a radiochelate with its serum protein binding potential and cellular-uptake-level. The correlation is investigated in this work by using five 99m Tc-amine-oxime chelates containing 2-NI group and another five containing aniline group (as control). The results indicate that the level of protein-and cellular-binding of a radiochelate increased with their lipophilicity which generally correlates with the lengthening of the alkyl chains on the backbone of the radiochelates. The greater lipophilicity of a radiochelate, the higher percentage it bound to serum proteins and cellular membrane. Our study also indicates that, in addition to lipophilicity, polarity of the constituents is also an important factor of determining the levels of serum protein binding and cellular accumulation of a radiochelate.

Recent Advances on Radionuclide Labeled Hypoxia-Imaging Agents

“…The mechanism of uptake was believed to be passive diffusion and the higher lipophilicity allowed the entry of the complex to cells more readily [49]. Li et al also reported that the level of protein-and cellular-binding of a series of 99m Tc-amine-oxime chelates containing 2-nitroimidazole group increased with their lipophilicity, which generally correlated with the length of the alkyl chains and the polarity of the substituents on the backbone of the radiochelates [50]. These results contradict with Hsia et al's, but, up to now, the knowledge of the mechanism of HL-91 retention is still very limited and remains unclear.…”