Functionally Versatile and Highly Stable Chelator for 111In and 177Lu: Proof-of-Principle Prostate-Specific Membrane Antigen Targeting

Abstract

Here, we present the synthesis and characterization of a new potentially nonadentate chelator H₄pypa and its bifunctional analogue ^tBu₄pypa-C7-NHS conjugated to prostate-specific membrane antigen (PSMA)-targeting peptidomimetic (Glu-urea-Lys). H₄pypa is very functionally versatile and biologically stable. Compared to the conventional chelators (e.g., DOTA, DTPA), H₄pypa has outstanding affinities for both ¹¹¹In (EC, t_1/2 ≈ 2.8 days) and ¹⁷⁷Lu (β^-,γ, t_1/2 ≈ 6.64 days). Its radiolabeled complexes were achieved at >98% radiochemical yield, RT within 10 min, at a ligand concentration as low as 10^-6 M, with excellent stability in human serum over at least 5-7 days (<1% transchelation). The thermodynamic stabilities of the [M(pypa)]^- complexes (M³⁺ = In³⁺, Lu³⁺, La³⁺) were dependent on the ionic radii, where the smaller In³⁺ has the highest pM value (30.5), followed by Lu³⁺ (22.6) and La³⁺ (19.9). All pM values are remarkably higher than those with DOTA, DTPA, H₄octapa, H₄octox, and H₄neunpa. 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 H₄pypa to a PSMA-targeting pharmacophore, proving that the bioconjugation sacrifices neither the tumor-targeting nor the chelation properties. The biodistribution profiles of ¹¹¹In- and ¹⁷⁷Lu-labeled tracers are different, but promising, with the ¹⁷⁷Lu analogue particularly outstanding.