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The Al 18 F-labeling approach offers a one-step access to radiofluorinated biomolecules by mimicking the labeling process for radiometals. Although these labeling conditions are considered to be mild compared to classic radiofluorinations, improvements of the chelating units have led to the discovery of (±)-H 3 F-labeling already at ambient temperature. While the suitability of RESCA , which allows Al 18 F-labeling, the cyclohexanediamine triazole (CHDT) moiety allows stable complexation of (±)-H 3 RESCA F-, 18 F-labeling, the cyclohexanediamine triazole (CHDT) moiety allows stable complexation of 68 Ga and 111 In. Three novel CHDT-functionalized PSMA inhibitors were synthesized and their Al 18 F-, 68 F-labeled PSMA ligands were characterized for their biodistribution in a LNCaP derived tumor xenograft mouse model by PET imaging. One radioligand, 111 In-labeled analogs were subjected to a detailed in vitro radiopharmacological characterization. Stability studies in vitro in human serum revealed among others a high kinetic inertness of all radiometal complexes. Furthermore, the Al 18 F-labeled PSMA ligands were characterized for their biodistribution in a LNCaP derived tumor xenograft mouse model by PET imaging. One radioligand, Al[ F, 18 F]F-CHDT-PSMA-1 , bearing a small azidoacetyl linker at the glutamate-urea-lysine motif, provided an in vivo performance comparable to that of [ 18 F]PSMA-1007 but with even higher tumor-to-blood and tumor-to-muscle ratios at 120 min p.i. Overall, our results highlight the suitability of the novel CHDT moiety for functionalization and radiolabeling of small molecules or peptides with Al 18 F, 68 Ga, and 111 In and the triazole ring seems to entail favorable pharmacokinetic properties for molecular imaging purposes.

To pursue the design of in vivo stable chelating systems for radiometals, a concise and straightforward method toolbox was developed combining NMR, isothermal titration calorimetry (ITC), and europium time-resolved laser-induced fluorescence spectroscopy (Eu-TRLFS). For this purpose, the macropa chelator was chosen, and Lu 3+ , La 3+ , Pb 2+ , Ra 2+ , and Ba 2+ were chosen as radiopharmaceutically relevant metal ions. They differ in charge (2+ and 3+) and coordination properties (main group vs lanthanides). 1 H NMR was used to determine four p K a values (±0.15; carboxylate functions, 2.40 and 3.13; amino functions, 6.80 and 7.73). Eu-TRLFS was used to validate the exclusive existence of the 1:1 M n + /ligand complex in the chosen pH range at tracer level concentrations. ITC measurements were accomplished to determine the resulting stability constants of the desired complexes, with log K values ranging from 18.5 for the Pb-mcp complex to 7.3 for the Lu-mcp complex. Density-functional-theory-calculated structures nicely mirror the complexes' order of stabilities by bonding features. Radiolabeling with macropa using ligand concentrations from 10 -3 to 10 -6 M was accomplished by pointing out the complex formation and stability ( 212 Pb > 133 La > 131 Ba ≈ 224 Ra > 177 Lu) by means of normal-phase thin-layer chromatography analyses.