Synthesis and evaluation of two novel 2-nitroimidazole derivatives as potential PET radioligands for tumor imaging

Abstract

Introduction Nitroimidazole (azomycin) derivatives labeled with radioisotopes have been developed as cancer imaging and radiotherapeutic agents based on the oncological hypoxic mechanism. By attaching nitroimidazole core with different functional groups, we synthesized new nitroimidazole derivatives, and evaluated their potentiality as tumor imaging agents. Methods Starting with commercially available 2-nitroimdazole, 2-fluoro-N-(2-(2-nitro-1H-imidazol-1-yl)ethyl)acetamide (NEFA, [19F]7) and 2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethyl 2-fluoroacetate (NEFT, [19F]8), as well as radiolabeling precursors - the bromo substituted analogs were quickly synthesized through a three-step synthetic pathway. The precursors were radiolabeled with [18F]F-/18-crown-6/KHCO3 in DMSO at 90 °C for 10 min followed by purification with an Oasis HLB cartridge. Biodistribution studies were carried out in EMT-6 tumor-bearing mice. The uptake (%ID/g) in tumors and normal tissues were measured at 30 min post injection. Liquid chromatography-electrospray ionization mass spectrometry (LC/MS) was used to distinguish metabolites from parent drugs in urine and plasma of rat injected with “cold” NEFA ([19F]7) and NEFT ([19F]8). Results Two radiotracers, [18F]NEFA ([18F]7) and [18F]NEFT ([18F]8), were prepared with average yields of 6-7% and 9-10% (no decay corrected). Radiochemical purity for both tracers was >95% as determined by HPLC. Biodistribution studies in EMT-6 tumor-bearing mice indicated that the tumor to blood and tumor to liver ratios of both [18F]7 (0.96, 0.98) and [18F]8 (0.61,1.10) at 30 min were higher than those observed for [18F]FMISO (1) (0.91, 0.59), a well-investigated azomycin type hypoxia radiotacer. LC/MS analysis demonstrated that fluoroacetate was the main in vivo metabolite for both NEFA ([19F]7) and NEFT ([19F]8). Conclusions In this research, two new fluorine-18 labeled 2-nitroimdazole derivatives, [18F]7 and [18F]8, both of which containing in vivo hydrolyzable group, were successfully prepared. Further biological evaluations are warranted to investigate their potential as PET radioligands for imaging tumor.

99mTc-HYNIC-MPG: A novel SPECT probe for targeting mutated EGFR

“…[7][8][9][10] They can only reflect the expression level of EGFR but not EGFR mutational status, however, it remains unresolved for EGFR TKI resistance and EGFR mutation in clinical practice. On the other hand, increasing attention has been paid onto the use of radionuclides-labeled small molecule TKIs to identify EGFR mutation in vivo, such as 18 F, 11 C, and 64 Cu, etc. ; [11][12][13] however, the result was not ideal yet.…”

“…18 Animals were given normal diet after injection. 19 Blood sample of 100 ll was through heart from 3 mice at different time points (1, 2, 4, 6, 12, 18 and 24 h), and centrifuged at 3500 rpm for 5 min to get the plasma.…”

KEMTUB012-NI2, a novel potent tubulysin analog that selectively targets hypoxic cancer cells and is potentiated by cytochrome p450 reductase downregulation

“…KEMTUB001 and KEMTUB012 were coupled via the terminal carboxylic group to compounds bearing a 2-nitroimidazole group (NI1, NI2, and NI3) to obtain tubulysin derivatives shown in Figure 1. In particular, both the tubulysin derivatives were conjugated to 2-(2-nitro-1 H -imidazol-1-yl)ethanamine, NI1 19. KEMTUB012 was also coupled to compounds NI2 and NI3, respectively, N -(3-aminopropyl)-2-(2-nitro-1 H -imidazol-1-yl)acetamide, and N-(6-aminohexyl)-2-(2-nitro-1 H -imidazol-1-yl)acetamide.…”

Facile and Efficient Synthesis of [18F]Fluoromisonidazole Using Novel 2-Nitroimidazole Derivatives

“…1,14 Therefore, nitroimidazole derivatives with 18 F are used to quantify hypoxia through PET. [15][16][17][18] Among the derivatives, [ is widely known and studied by many medical groups. 14,[19][20][21][22][23] We were interested in developing a useful method for the synthesis of [ 18 F]FMISO for higher overall synthetic yield along with a higher radio synthetic yield.…”