Proton Affinity Calculations for MRI Ligands.

Abstract

Molecular modelling techniques and the semiempirical quantum mechanical method MOPAC (AM1) have been used to calculate proton affinities (E(pa)) for the three basic nitrogens in four polyaminocarboxylate ligands: DTPA (1,4,7-triazaheptane-1,1,4,7,7-pentaacetic acid), DTPA-BMA 1,7-bis(methyl-carbamoylmethyl)-1,4,7-triazaheptane-1,4,7-triacetic acid], DTPA-US1 {[}1,1-bis-(methylcarbamoylmethyl)-1,4.7-triazaheptane-4.7,7-triacetic acid] and DTPA-US2 {[}1,4-bis(methylcarbamoylmethyl)-1,4,7-triazaheptane-1,7,7-triacetic acid]. The calculated E(pa) values suggest distinctions between the compounds regarding the first protonation step. It is easier to protonate a terminal nitrogen relative 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 patterns 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 of DTPA-derivatives might be enhanced.