Synthesis and evaluation of an ¹⁸F‐labeled trifluoroborate derivative of 2‐nitroimidazole for imaging tumor hypoxia with positron emission tomography

Abstract

2-Nitroimidazole-based hypoxia imaging tracers such as F-FMISO are normally imaged at late time points (several hours post-injection) due to their slow clearance from background tissues. Here, we investigated if a hydrophilic zwitterion-based ammoniomethyl-trifluoroborate derivative of 2-nitroimidazole, F-AmBF -Bu-2NI, could have the potential to image tumor hypoxia at earlier time points. AmBF -Bu-2NI was prepared in 4 steps. F labeling was conducted via F- F isotope exchange reaction, and F-AmBF -Bu-2NI was obtained in 14.8 ± 0.4% (n = 3) decay-corrected radiochemical yield with 24.5 ± 5.2 GBq/μmol specific activity and >99% radiochemical purity. Imaging and biodistribution studies in HT-29 tumor-bearing mice showed that F-AmBF -Bu-2NI cleared quickly from blood and was excreted via the hepatobiliary and renal pathways. However, the tumor was not visualized in PET images until 3 hours post-injection due to low tumor uptake (0.54 ± 0.13 and 0.19 ± 0.04%ID/g at 1 and 3 hours post-injection, respectively). The low tumor uptake is likely due to the highly hydrophilic motif of ammoniomethyl-trifluoroborate that prevents free diffusion of F-AmBF -Bu-2NI across the cell membrane. Our results suggest that highly hydrophilic F-labeled ammoniomethyl-trifluoroborate derivatives might not be suitable for imaging intracellular targets including nitroreductase, a common tumor hypoxia imaging target.

Hypoxia and the phenomenon of immune exclusion

“…18F-FMISO is the most widely used tracer but is found at a relatively low concentration in tumors. Moreover, it is normally imaged several hours post-injection, due to its slow clearance from background tissues [358][359][360]. These circumstances could render the image acquisition challenging.…”

Synthesis and Evaluation of [18F]FEtLos and [18F]AMBF3Los as Novel 18F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors

“…This approach was previously used for radiolabeling peptides using high activities of [ 18 F]F − and very low amounts of precursor (75-100 nmol), within 30 min with a radiochemical purity >99%, a high molar activity (68-148 GBq/µmol), a radiochemical yield of 20-28%, with HPLC-free purification [34,38,53]. Small [ 18 F]AMBF 3 -conjugated molecules were also synthesized with a radiochemical yield of 14.8 ± 0.4% with a molar activity of 24.5 ± 5.2 GBq/µmol and radiochemical purity >99% [54]. Taking into account that the reaction medium is acid, a significant amount of [ 18 F]F − is lost by volatilization as [ 18 F]hydrogen fluoride during the labeling reaction under vacuum and heating.…”

Recent Developments in PET and SPECT Radiotracers as Radiopharmaceuticals for Hypoxia Tumors

“…An in vitro cellular uptake study of radiot in MCF-7 cells under hypoxic and normoxic conditions indicated that th pounds showed no significant difference in cellular uptake under hypox conditions; thus, [ 18 F]1a-c had less selectivity toward hypoxia cells [ 18 F]FMISO. F]4) for ima poxia (Figure 5) [131]. [ 18 F]4 had a logp value of −1.52 ± 0.02 and remained plasma for 1 h. At 1 h p.i., the in vivo biodistribution of [ 18 F]4 in mice with demonstrated minimal uptake in the tumor (0.54 ± 0.13%ID/g), leading t tumor/muscle and tumor/blood ratios (0.51 ± 0.25 and 0.99 ± 0.32, respectiv the tumor uptake was reduced to 0.19 ± 0.04%ID/g, whereas tumor/m mor/blood ratios increased (0.92 ± 0.08 and 2.62 ± 1.02, respectively).…”

“…An in vitro cellular uptake study of radiotracers [ 18 F]1a-c in MCF-7 cells under hypoxic and normoxic conditions indicated that these three compounds showed no significant difference in cellular uptake under hypoxic and aerobic conditions; thus, [ 18 F]1a-c had less selectivity toward hypoxia cells compared to [ 18 F]FMISO. Lin and co-workers developed 18 F-labeled zwitterion-based ammoniomethyl-trifluoroborate bearing 2-nitroimidazole ( 18 F-AmBF3-Bu-2NI, [ 18 F]4) for imaging tumor hypoxia (Figure 5) [131]. [ 18 F]4 had a logp value of −1.52 ± 0.02 and remained intact in mouse plasma for 1 h. At 1 h p.i., the in vivo biodistribution of [ 18 F]4 in mice with HT-29 tumors demonstrated minimal uptake in the tumor (0.54 ± 0.13%ID/g), leading to low ratios of tumor/muscle and tumor/blood ratios (0.51 ± 0.25 and 0.99 ± 0.32, respectively).…”