Synthesis of ¹⁸F‐Labelled β‐Lactams by Using the Kinugasa Reaction

Abstract

Owing to their broad spectrum of biological activities and low toxicity, β-lactams are attractive lead structures for the design of novel molecular probes. However, the synthesis of positron emission tomography (PET)-isotope-labelled β-lactams has not yet been reported. Herein, we describe the simple preparation of radiofluorinated β-lactams by using the fast Kinugasa reaction between (18)F-labelled nitrone [(18)F]-1 and alkynes of different reactivity. Additionally, (18)F-labelled fused β-lactams were obtained through the reaction of a cyclic nitrone 7 with radiofluorinated alkynes [(18)F]-6 a,b. Radiochemical yields of the Kinugasa reaction products could be significantly increased by the use of different Cu(I) ligands, which additionally allowed a reduction in the amount of precursor and/or reaction time. Model radiofluorinated β-lactam-peptide and protein conjugates ([(18)F]-10 and (18)F-labelled BSA conjugate) were efficiently obtained in high yield under mild conditions (aq. MeCN, ambient temperature) within a short reaction time, demonstrating the suitability of the developed method for radiolabelling of sensitive molecules such as biopolymers.

18F-Labeling Using Click Cycloadditions

“…The latest developments in metal-free 18 F-click cycloadditions have been reported by Zlatopolskiy et al [19–21] (Table 3). In a first approach, the 18 F-labeled building block C-(4-[ 18 F]fluorophenyl)-N-phenyl nitrone was developed to form 18 F-isoxazolidines via high-yielding [3+2]cycloadditions with various maleimides [19].…”

“…In a very recent report, Zlatopolskiy and coworkers applied their 18 F-labeled nitrone, C-(4-[ 18 F]fluorophenyl)-N-phenyl nitrone, for the first formation of 18 F-labeled β -lactames via the CuI-catalyzed Kinugasa reaction [21] (Table 3). The optimized reactions went smooth under very mild conditions to give the 18 F-labeled model β -lactames in high RCY and various isomeric mixtures of the trans - and cis -product.…”

“…Moreover, the dipeptide β -Ala-Phe-OMe was propiolated and used in this radio-Kinugasa reaction to give excellent RCY of 85% of the 18 F-labeled dipeptide under very mild conditions (aqueous solution, room temperature) [21]. Similarly, this new method was successfully transferred to the 18 F-labeling of proteins.…”

“…Very recently, new versions of 18 F-click cycloadditions are added to the range of reactions [19–25]. In this line, the first 18 F-labeled β -lactame became available via a new radio -Kinugasa reaction [21]. …”

Minimalist approach meets green chemistry: Synthesis of18F‐ labeled (hetero)aromatics in pure ethanol

“…The latter reduces radiation exposure of the personnel and at the same time simplifies cGMP PET tracer production. Nevertheless, in recent years several novel fluorination techniques for the preparation of radiofluorinated compounds have been reported . In particular, several efficient transition metal‐mediated radiofluorination protocols have been published …”