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

Here, we present the synthesis and characterization of a new potentially nonadentate chelator H(4)pypa and its bifunctional analogue (t)Bu(4)pypa-C7-NHS conjugated to prostate-specific membrane antigen (PSMA)-targeting peptidomimetic (Glu-urea-Lys). H(4)pypa is very functionally versatile and biologically stable. Compared to the conventional chelators (e.g., DOTA, DTPA), H(4)pypa has outstanding affinities for both In-111 (EC, t(1/2) approximate to 2.8 days) and Lu-177 (beta-, gamma, t(1/2) approximate to 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, H(4)octapa, H(4)octox, and H(4)neunpa. 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 H(4)pypa to a PSMA-targeting pharmacophore, proving that the bioconjugation sacrifices neither the tumor-targeting nor the chelation properties. The biodistribution profiles of In-111-and Lu-177-labeled tracers are different, but promising, with the Lu-177 analogue particularly outstanding.