In Vivo Ester Hydrolysis as a New Approach in Development of Positron Emission Tomography Tracers for Imaging Hypoxia

Abstract

Hypoxia is an important biochemical and physiological condition associated with uncontrolled growth of tumor. Measurement of hypoxia in tumor tissue may be useful in characterization of tumor progression and monitoring drug treatment.[ 18 F]FMISO is the most widely employed radiotracer for imaging of hypoxic tissue with positron emission tomography (PET). However, it showed relatively low uptake in hypoxic tissues, which led to low target-to-background contrast in PET images. To overcome these shortcomings, two novel 2-fluoroproprioic acid esters, nitroimidazole derivatives 2-fluoropropionic acid 2-(2nitro-imidazol-1-yl)-ethyl ester (FNPFT, [ 19 F]5) and 2-fluoropropionic acid 2-(2-methyl-5-nitro-imidazol-1-yl)-ethyl ester (FMNPFT, [ 19 F]8), were prepared and tested. Radiolabeling of [ 18 F]5 and [ 18 F]8 was accomplished in 45 min (radiochemical purity >95%, the decay-corrected radiochemical yield of [ 18 F]5 was 11 ± 2%, and that of [ 18 F]8 was 13 ± 2%, n = 5). In vitro cell uptake studies using EMT-6 tumor cells showed that both radiotracers [ 18 F]5 and [ 18 F]8 displayed significantly higher uptake in hypoxic cells than those under normoxic condition, while 2-[ 18 F]fluoropropionic acid (2-[ 18 F]FPA) displayed no difference. Biodistribution studies in mice bearing EMT-6 tumor showed that [ 18 F]5, [ 18 F]8, and 2-[ 18 F]FPA displayed similar tumor and major organ uptakes. Tumor uptake values for all three agents were higher than those of [ 18 F]FMISO, respectively (P < 0.05). This is likely due to a rapid in vivo hydrolysis of [ 18 F]5 and [ 18 F]8 to their metabolite, 2-[ 18 F]FPA. Micro PET imaging studies in the same EMT-6 implanted mice tumor model also demonstrated that both [ 18 F]5 and [ 18 F]8 displayed similar tumor uptake comparable to that of 2-[ 18 F]FPA. In conclusion, two new fluorine-18 labeled nitroimidazole derivatives, [ 18 F]5 and [ 18 F]8, showed good tumor uptakes in mice bearing EMT-6 tumor. However, in vivo biodistribution results suggested that they were more likely reflect the predominance of in vivo produced metabolite, 2-[ 18 F]FPA, which may not be related to tumor hypoxic condition.

Preparation and Bioevaluation of Novel 99mTc-Labeled Complexes with a 2-Nitroimidazole HYNIC Derivative for Imaging Tumor Hypoxia

“…High liver uptake and a relatively low tumor/liver ratio are common disadvantages for most nitroimidazole radiotracers for imaging tumor hypoxia. For example, the tumor-to-liver ratio of [ 18 F]FMISO is merely 0.82 in EMT-6 tumor-bearing mice at 120 min post-injection [11], which is less than half the ratio of [ 99m Tc]Tc-tricine-TPPTS-HYNICNM (1.95). Compared to [ 18 F]FMISO, as [ 99m Tc]Tc-tricine-TPPTS-HYNICNM showed extremely low uptake in other major organs, it also displayed a higher tumor to non-targeted ratios (tumor/muscle: 5.05 vs. 1.45 at 2 h post-injection).…”

“…Several SPECT and PET radiotracers with nitroimidazole have been reported to date and have attracted attention [10][11][12][13][14][15][16][17][18][19][20][21]. [ 18 F]FMISO is one of the most widely used PET radiotracers for imaging hypoxia [22].…”

68Ga/177Lu-Labeled Bivalent Agents for Targeting Hypoxia and PSMA-Binding in Prostate Cancer

“…(25). Compound 25 was prepared from AAZTA (tBu) 4 (149 mg, 0.223 mmol), HATU (161 mg, 0.423 mmol), DIPEA (37.1 mg, 0.287 mmol), and compound 24 following the same procedure described for compound 11 as a yellow oil (71.9 mg, yield: 34% (26). To a solution of 25 (56.4 mg, 0.058 mmol) in 3 mL of THF was added The resulting mixture was stirred at r.t. for 2 h, then heated to 50 °C and stirred for an additional 30 min to obtain [ nat Lu]Lu-8.…”

Recent Advancements on Self‐Immolative System Based on Dynamic Covalent Bonds for Delivering Heterogeneous Payloads

“…Besides from decreasing the drug accumulation, tumor hypoxia can also increase the cells’ multidrug resistance. Fortunately, several supramolecular covalent bonds or groups can be integrated into self‐immolative design as a trigger for hypoxia activation, for instance, azo benzene, [ 62 ] nitroimidazole, [ 63 ] or nitrobenzene. [ 64 ] Wang et al described an azo ‐based near‐infrared fluorescent nitrogen mustards‐dye conjugate for tracking hypoxia‐activated cancer chemotherapy in vivo.…”