TPEN, N,N,N',N'-tetrakis(2-pyridylmethyl)-1,2-ethylenediamine, recognized as a multidentate ligand with six nitrogen donors for coordination with various metal ions, is employed as an extracting agent for soft metal ions and trivalent minor actinides such as Am-III and Cm-III. This review highlights the synthetic design of TPEN derivatives by introduction of peripheral substituents into the pyridine ring and modification of heteroaromatic ring structures for the purpose of improving the extraction performance.