Auto-assembling of ditopic macrocyclic lanthanide chelates with transition-metal ions. Rigid multimetallic high relaxivity contrast agents for magnetic resonance Imaging

PhenHDO3A is a ditopic ligand featuring a tetraazacyclododecane unit substituted by three acetate arms and one 6-hydroxy-5,6-dihydro-1,10-phenanthroline group (PhenHDO3A = rel-10-[(5R, 6R)-5,6-dihydro-6-hydroxy-1,10-phenantholin- 5- yl)- 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid). This ligand was specially designed so as to obtain highly stable heteropolymetallic assemblies. PhenHDO3A has been prepared starting from phenanthroline epoxide and either a triprotected tetraazacyclododecane or tert-butyl triester of N, N', N-tetraazacyclododecanetriacetic acid. The latter yields PhenHDO3A in a single step. PhenHDO3A forms kinetically stable lanthanide complexes (acid-catalyzed kinetic constant k(H) = (1.2 +/- 0.2) x 10(-3) s(-1) M-1) whose solution structure has been deduced from a quantitative analysis of the paramagnetic shifts and the longitudinal relaxation times of the proton nuclei of YbPhenHDO3A. The alcohol group of the dihydro-phenanthroline unit remains coordinated to the encapsulated metal ion despite the steric crowding brought about by this group. Furthermore, the complexes are monohydrated, as shown by luminescence lifetime measurements on EuPhenHDO3A solutions. Relaxivity titrations at 20 MHz clearly indicate that the phenanthroline unit of GdPhenHDO3A is available for the spontaneous formation of highly stable tris complexes with the Fe2+ and Ni2+ ions. The water-exchange times and the rotational correlation times of GdPhenHDO3A and Fe(GdPhenHDO3A)(3)(2+) have been deduced from variable temperature O-17 NMR studies and from nuclear relaxation dispersion curves. Despite rather slow water-exchange rates (tau(0)(m) = 1.0 - 1.2 x 10(-6) s), relaxivity gains of 90% have been observed upon the formation of the heterometallic tris complexes. The latter rotate about four times more slowly (tau(0)(r) = 398 ps) than the monomeric unit (tau(0)(r) = 105 ps) and their relaxivity is, accordingly, twice as high. The relaxivity of the tris complexes between 10 and 50 MHz is comparable to relaxivities reported for Gd3+-containing dendrimers of much higher molecular weights. The high relaxivity of the tris-PhenHDO3A lanthanide complexes is attributed to their internal rigidity.