Decadentate Acyclic Chelators for Lanthanum Radiopharmaceuticals

Two decadentate acyclic chelators bearing four picolinic acid groups appended on either an ethylenediamine (H₄TPAEN) or a trans-1,2-cyclohexyldiamine (H₄TPADAC) unit were explored as candidates for lanthanum-based radiopharmaceutical development. The two chelators form ten-coordinated complexes with La³⁺ in the solid state, as evidenced by the corresponding X-ray structures and solution NMR studies. The La³⁺ complexes of TPAEN^4- and TPADAC^4- are characterized by high thermodynamic stability constants of log K_LaL = 19.16(8) and 19.55(1), respectively. Kinetics studies indicate that the complexes dissociate following the acid-catalyzed and Cu²⁺-assisted pathways. Quantitative radiolabeling of both chelators with [¹³⁵La]La³⁺ was achieved at pH ∼ 4-5 using straightforward protocols and low concentrations of the chelator (3 μM). Both in vitro and in vivo studies indicate that the [¹³⁵La]La³⁺ complex of TPAEN^4- is significantly more stable than the TPADAC^4- analogue, with the former remaining intact and stable even after 60 min in vivo when injected to healthy mice.