Towards an Improved Design of MRI Contrast Agents: Synthesis and Relaxometric Characterisation of Gd‐HPDO3A Analogues

Abstract

The properties of LnIII‐HPDO3A complexes as relaxation enhancers and paraCEST agents are essentially related to the hydroxylpropyl moiety. A series of three HPDO3A derivatives, with small modifications to the hydroxyl arm, were herein investigated to understand how heightened control can be gained over the parameters involved in the design of these agents. A full 1H and 17O‐NMR relaxometric analysis was conducted and demonstrated that increasing the length of the OH group from the lanthanide centre significantly enhanced the water exchange rate of the gadolinium complex, but with a subsequent reduction in kinetic stability. Alternatively, the introduction of an additional methyl group, which increased the steric bulk around the OH moiety, resulted in the formation of almost exclusively the TSAP isomer (95 %) as identified by 1H‐NMR of the europium complex. The gadolinium analogue of this complex also exhibited a very fast water exchange rate, but with no detectable loss of kinetic stability. This complex therefore demonstrates a notable improvement over Gd‐HPDO3A.

Supramolecular adducts between macrocyclic Gd(iii) complexes and polyaromatic systems: a route to enhance the relaxivity through the formation of hydrophobic interactions

“…*  M was fixed to the value of the derived weighted average of τ M for the two SAP/TSAP isomers. 27,28 The obtained profile of the Gd-HPDO3A/HPTS adduct was nicely fitted to the values calculated based on the established Solomon-Bloembergen-Morgan (SBM) theory and reported in table 2. When compared with data obtained for parent Gd-HPDO3A, two parameters appear to be responsible for the relaxation enhancement observed in the presence of HPTS, namely  R that increases from 69 to 94 ps and the number of second sphere water molecules (qss) that moves from 0 to 2.5, respectively.…”

“…aThe following parameters were fixed during the fitting procedure: q = 1, r GdH = 3.1 Å, a GdH = 3.8 Å, D = 2.24 × 10 −5 cm 2 s −1 , r GdH (2 nd sphere) = 4 Å, τ c (2 nd sphere) = 60 ps.b τ M was fixed to the value of the derived weighted average of τ M for the two SAP/TSAP isomers. 27,28 …”

“…b τ M was fixed to the value of the derived weighted average of τ M for the two SAP/TSAP isomers. 27,28 …”

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“…The 17 O- R 2 vs T profile measured for an aqueous solution of Gd-L1 (Figure A) has the typical shape observed in the presence of two species/isomers in solution. As for the parent Gd-HPDO3A, they can be associated with TSAP and SAP diastereoisomers for which a TSAP/SAP ratio of 30/70 was reported. , For Gd-L1, the isomer distribution was found to be 60% TSAP and 40% SAP, in agreement with the ratio observed for Eu-L1 (Figure S7 where the mono- and bi-dimensional 1 H NMR spectra are reported). The analysis of the 17 O- R 2 vs T profile allowed to calculate exchange lifetimes of 1.9 and 470 ns for TSAP and SAP isomers, respectively, which resulted in a weighted average of 189 ns.…”

“…Notably, the higher proportion of the TSAP isomer is responsible for a substantially shorter water exchange lifetime than the one determined for Gd-HPDO3A, where the average τ M was calculated to be 450 ns. 48 A rapid exchange of the coordinated water molecule is definitely a favorable feature for achieving high relaxivities upon binding to macromolecular sys- tems. 20,37,38 The 1 H-NMRD profile of Gd-L1 in water (Figure 5B) was fitted by considering the contribution from 1.5 coordinated water molecules, i.e., one inner sphere water molecule plus the proton of the coordinating alcoholic group whose involvement in the exchange with water appears to occur already at neutral pH.…”