PROTON AFFINITY CALCULATIONS FOR MRI LIGANDS

Molecular modelling techniques and the semiempirical quantum mechanica l method MOPAC (AM1) have been used to calculate proton affinities (E( pa)) for the three basic nitrogens in four polyaminocarboxylate ligand s: DTPA (1,4,7-triazaheptane-1,1,4,7,7-pentaacetic acid), DTPA-BMA rba moylmethyl)-1,4,7-triazaheptane-1,4,7-triacetic acid!, DTPA-US1 rbamoy lmethyl)-1,4.7-triazaheptane-4.7,7-triacetic acid! and DTPA-US2 rbamoy lmethyl)-1,4,7-triazaheptane-1,7,7-triacetic acid!. The calculated E(p a) values suggest distinctions between the compounds regarding the fir st protonation step. It is easier to protonate a terminal nitrogen rel ative to the central nitrogen in DTPA and in DTPA-US2. In DTPA-BMA the situation is the opposite, whereas the E(pa) values are fairly equal in DTPA-US1. Inductive effects and differences in hydrogen-bonding pat terns involving the protonated ligands may explain these findings. The calculated E(pa)s offer an explanation for the low second protonation constant found in DTPA bis-amides compared with DTPA; protonation of the second nitrogen involves movement of a larger fraction of protons from the central nitrogen to the other terminal nitrogen in the former case. Since the pK(a) values are closely tied to the stability of the corresponding Gd-chelates, this gives clues as to how the stability o f DTPA-derivatives might be enhanced.