Functionally Versatile and Highly Stable Chelator for In and Lu: Proof-of-Principle Prostate-Specific Membrane Antigen Targeting.

Here, we present the synthesis and characterization of a new potentially nonadentate chelator Hpypa and its bifunctional analogue Bupypa-C7-NHS conjugated to prostate-specific membrane antigen (PSMA)-targeting peptidomimetic (Glu-urea-Lys). Hpypa is very functionally versatile and biologically stable. Compared to the conventional chelators (e.g., DOTA, DTPA), Hpypa has outstanding affinities for both In (EC, t ≈ 2.8 days) and Lu (β,γ, t ≈ 6.64 days). Its radiolabeled complexes were achieved at >98% radiochemical yield, RT within 10 min, at a ligand concentration as low as 10 M, with excellent stability in human serum over at least 5-7 days (<1% transchelation). The thermodynamic stabilities of the [M(pypa)] complexes (M = In, Lu, La) were dependent on the ionic radii, where the smaller In has the highest pM value (30.5), followed by Lu (22.6) and La (19.9). All pM values are remarkably higher than those with DOTA, DTPA, Hoctapa, Hoctox, and Hneunpa. Moreover, the facile and versatile bifunctionalization enabled by the p-OH group in the central pyridyl bridge of the pypa scaffold (compound 14) allows incorporation of a variety of linkers for bioconjugation through easy nucleophilic substitution. In this work, an alkyl linker was selected to couple Hpypa to a PSMA-targeting pharmacophore, proving that the bioconjugation sacrifices neither the tumor-targeting nor the chelation properties. The biodistribution profiles of In- and Lu-labeled tracers are different, but promising, with the Lu analogue particularly outstanding.