Although a small peptidomimetic conjugate usually has higher tolerance to the harsh radiolabeling conditions (e.g., 60–90 ☌ for 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, DOTA, Chart 1), fast and quantitative radiolabeling at room temperature facilitates handling and avoids potential degradation of the product. The biodistribution profiles of 111In- and 177Lu-labeled tracers are different, but promising, with the 177Lu analogue particularly outstanding.Īn ideal chelator should possess rapid complexation kinetics and strong affinity for the radiometal ion at mild conditions (RT, <15 min complexation), as well as high versatility of linker incorporation (i.e., bifunctionalization) without sacrificing the coordination integrity. In this work, an alkyl linker was selected to couple H 4pypa to a PSMA-targeting pharmacophore, proving that the bioconjugation sacrifices neither the tumor-targeting nor the chelation properties. 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. All pM values are remarkably higher than those with DOTA, DTPA, H 4octapa, H 4octox, and H 4neunpa. The thermodynamic stabilities of the − complexes (M 3+ = In 3+, Lu 3+, La 3+) were dependent on the ionic radii, where the smaller In 3+ has the highest pM value (30.5), followed by Lu 3+ (22.6) and La 3+ (19.9). 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). Compared to the conventional chelators (e.g., DOTA, DTPA), H 4pypa has outstanding affinities for both 111In (EC, t 1/2 ≈ 2.8 days) and 177Lu (β –,γ, t 1/2 ≈ 6.64 days). H 4pypa is very functionally versatile and biologically stable.

Here, we present the synthesis and characterization of a new potentially nonadentate chelator H 4pypa and its bifunctional analogue tBu 4pypa-C7-NHS conjugated to prostate-specific membrane antigen (PSMA)-targeting peptidomimetic (Glu-urea-Lys).

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