A novel versatile precursor suitable for ¹⁸F‐radiolabeling via “click chemistry”

Abstract

As an effort to improve F-radiolabeling of biomolecules in method robustness and versatility, we report the synthesis and radiolabeling of a new azido precursor potentially useful for the so-called "click reaction," in particular the ligand-free version of the copper(I)-catalyzed alkyne-azide cycloaddition. The new azido precursor may help to overcome problems sometimes exhibited by most of the currently used analogues, as it is safe to handle and it displays long-term chemical stability, thus facilitating the development of new radiolabeling procedures. Moreover, the formed F-labeled 1,2,3-triazole is potentially metabolically stable and could enhance the in vivo circulation time. The above azido precursor was successfully radiolabeled with F, with 51% radiochemical yield (nondecay-corrected). As a proof of concept, the F-labeled azide was then tested with a suitable alkyne functionalized aminoacid (l-propargylglycine), showing 94% of conversion, and a final radiochemical yield of 27% (>99% radiochemical purity), nondecay-corrected, with a total preparation time of 104 minutes.

Synthesis and automated fluorine‐18 radiolabeling of new PSMA‐617 derivatives with a CuAAC radiosynthetic approach

“…Compared with mesylate and tosylate, iodine showed better results in terms of yield and purity during fluorine-18 substitution reaction. 31 [ 18 F]Fluorination and subsequent CuAAC reaction were performed and automated on a Trasis-AllinOne radiosynthesis system. Fluorine substitution was carried out on iodo-precursor 12 at 100 C, for 20 min, obtaining a crude mixture containing the desired [ 18 F]13 together with byproducts deriving from hydrolysis and elimination reactions, which was then passed through a tC18 Sep-Pak cartridge.…”

“…The resulting [ 18 F]fluoroazide was initially conjugated with L-propargylglycine (a suitable alkyne-functionalized glycine), in order to test the CuAAC reaction. 31…”

Click Chemistry and Radiochemistry: An Update

“…238 More recently, an 225 Ac-based approach to PRIT based on 5B1-TCO and 225 Ac-DOTA-PEG 7 -Tz yielded very promising results in a murine model of pancreatic cancer, boasting a tumoral dose rate (1994 Gy/ MBq) and a tumor-to-blood therapeutic index (24.1) higher than that of a traditional 225 Ac-labeled radioimmunoconjugate (1377 Gy/MBq and 11.4, respectively). 239 Finally, a theranostic approach to IEDDA-based PRIT based on the radioisotopic pair of 64 Cu and 67 Cu was recently developed in a murine model of colorectal cancer (Figure 21). 237 Here, the initial administration of a TCO-bearing immunoconjugate (i.e., huA33-TCO) was followed by the injection of not one but two radioligands: first, a 64 Cu-labeled probe for theranostic PET and then, 24 h later, a 67 Cu-labeled Tz for therapy.…”

Synthesis of 1,4-Biphenyl-triazole Derivatives as Possible 17β-HSD1 Inhibitors: An in Silico Study

“…29 Thus, 1,2,3-triazole scaffolds are of interest for drug development because these systems act as a bioisostere of different functional groups such as amide, ester, carboxylic acid, and heterocycle, 30 and they also are highly stable under basic, acidic, reductive, oxidative, and enzymatic conditions due to high aromatization. 31,32 The 1,2,3-triazole ring system can be easily built via triazoles in high regioselectivity, broad substrate scope, favorable kinetic, excellent yield, insensitivity toward oxygen and water, and pure product isolation. This reaction can be performed in the presence of a wide variety of functional groups, facile and gentle conditions, wide pH range tolerance, and compatibility with a variety of solvents.…”

“…Their importance in the field of medicinal chemistry is due to high dipole moment, rigidity, and capability to bind with various kinds of enzymes and receptors via weak interactions such as hydrogen bonds, coordination bonds, ion–dipole, dipole–dipole, and cation−π and π stacking interactions when they bind with the biological target . Thus, 1,2,3-triazole scaffolds are of interest for drug development because these systems act as a bioisostere of different functional groups such as amide, ester, carboxylic acid, and heterocycle, and they also are highly stable under basic, acidic, reductive, oxidative, and enzymatic conditions due to high aromatization. , …”