Sc(III) Complexes of Pyclen Derivative Ligands as Probes for Hypoxia: Synthesis, Chemical Characterization, 44 Sc‐Radiolabeling, and Preclinical Assessment

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Abstract
Rigid pyclen derivative ligands bearing hypoxia‐sensitive nitroimidazole (NI) pendants, PC2A‐Ph‐NI (hexadentate) and PC2AM‐NI (heptadentate), were synthesized, radiolabeled with 44 Sc(III), and evaluated under preclinical circumstances. Physicochemical characterization was carried out using the structurally related model ligand, PC2AM nBu , by multinuclear NMR, UV‐Vis spectroscopy, and pH‐potentiometry. Sc(III) ion was found to form a stable complex with PC2AM nBu (log K ScL = 19.53(4); pSc = 19.32), in a reasonably fast reaction, with outstanding inertness ( t 1/2 = 529 hours in 1 M HClO 4 ). The [Sc(PC2AM nBu )] + complex can coordinate fluoride (log K ScLF = 2.5(2)), and the ternary complex is remarkably inert against fluoride exchange. Based on these results, the PC2A‐mono(amide) platform seems to be a promising Sc(III)‐binder, paving the way for the labeling of NI‐containing ligands with 44 Sc(III). Followed by successful radiolabeling with the positron‐emitting 44 Sc isotope, labeling yields of 92% and over 99% were evidenced for [ 44 Sc][Sc(PC2AM‐NI)] + and [ 44 Sc][Sc(PC2A‐Ph‐NI)] + ; respectively, at 95 °C and 15 minutes; moreover, after purification, the radiochemical purity exceeded 99%. Both radiocomplexes remained stable in rat blood serum for at least 4 hours and exhibited high resistance toward transmetalation and transchelation processes. MicroPET imaging with preclinical models of B16‐F10 mouse melanoma was conducted to assess the tumor targeting capability and the in vivo biodistribution pattern of [ 44 Sc][Sc(PC2AM‐NI)] and [ 44 Sc][Sc(PC2A‐Ph‐NI)] + radiopharmaceuticals. Given the higher tumor uptakes of [ 44 Sc][Sc(PC2A‐Ph‐NI)] + with decreasing off‐target activity and related better tumor/noise ratios, we may conclude that the diagnostic potential of the PC2A‐Ph‐NI derivative outperforms that of the [ 44 Sc][Sc(PC2AM‐NI)] + .
Funding Information
  • National Research, Development and Innovation Office (NKFIH K‐134694)
  • National Research, Development and Innovation Office (ADVANCED 152778)

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