OPTIMIZED SYNTHESIS, STRUCTURE, AND SOLUTION DYNAMICS OF 1,4,7,10-TETRAAZACYCLODODECANE-1,4,7,10-TETRAKIS(METHYLENEPHOSPHONIC ACID) (H8DOTP)

There is an emerging interest in the application of polyazamacrocylic polymethylenephosphonate ligands as effective metal ion chelators for divalent and trivalent metal ions. One recently reported ligand that is rapidly finding many applications in radiopharmaceuticals, medical imaging, and spectroscopy is DOTP (H8DOTP = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phosphonic acid).1-3 The acid-base and metal complexation properties of this ligand have been reported1,2 and some of the lanthanide-DOTP complexes have found use as NMR shift and relaxation reagents for proteins4,5 and for biological cations.6-8 One complex, TmDOTP5-, has emerged as perhaps the most favorable Na-23 shift reagent (SR) available for perfused tissues9-11 and for in vivo animal spectroscopy and imaging studies.12-14 The first preparation of H8DOTP was reported15 in 1984, and since then, at least four similar synthetic procedures for preparing H8DOTP have appeared,2,5,6,16 each leading to different yields or products with subtly differing chemical characteristics. Our goal has been to develop a simple, high-yield synthetic procedure for DOTP that may be easily followed by others interested in using this ligand. We report here the X-ray crystal structure of H8DOTP, a temperature-dependent P-31 NMR study which shows that the solution structure of the ligand may be similar to that found in the solid-state, and a simple procedure for preparing this ligand it its purest form.