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

2019 
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, t1/2 ≈ 2.8 days) and 177Lu (β–,γ, t1/2 ≈ 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 faci...
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