Hetero-tripodal hydroxypyridonate gadolinium complexes: Syntheses, relaxometric properties, water exchange dynamics, and human serum albumin binding

The synthesis and relaxometric properties of hetero-tripodal hydroxypyridonate-terephthalamide gadolinium (Gd³⁺) chelates with differing structural features for probing human serum albumin (HSA) interactions are reported. The Gd³⁺ complexes are divided into two series. The first series (3-5) features a benzyl derivative connected to the hydroxypyridonate (HOPO) moiety. The second series of complexes (6-10) has the common feature of a poly(ethylene glycol) (PEG) attached to the terephthalamide (TAM) moiety and is nonbenzylated. The water exchange of the complexes is in the fast exchange regime with rates (k_ex) in the range 0.45-1.11 × 10⁸ s^-1. The complexes have a moderate interaction with HSA with association constants (K_A's) in the range 0.7-8.6 × 10³ M^-1. Protein binding results in an enhancement in proton relaxivity from 7.7-10.4 mM^-1 s^-1 (r₁p) to 15-29 mM^-1 s^-1 (r_1p^b). It is concluded that the interaction of the complexes with HSA (i) is enhanced by the presence of benzyl groups, (ii) is entropically driven, and (iii) results in a lower hydration number (q).