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 TPAEN4– and TPADAC4– are characterized
by high thermodynamic stability constants of log KLaL = 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 TPAEN4– is significantly
more stable than the TPADAC4– analogue, with the
former remaining intact and stable even after 60 min in vivo when injected to healthy mice.