Preclinical Assessment of the Safety of an ¹⁸F-labeled MCT1/MCT4 Inhibitor in a Swine Model for PET/CT Imaging of Cancer Metabolism

Take-Away Points

• ■ Major Focus: Safety assessment of a radioligand targeting MCT1/MCT4 for PET/CT imaging of cancer metabolism.

• ■ Key Result: Administration of fluorine 18 (¹⁸F)-FACH in a swine preclinical model was safe, and an effective dose of 12.4 μSv/MBq in swine, translating to 20.6 μSv/MBq in humans, was determined.

• ■ Impact: Further characterization of ¹⁸F-FACH is warranted for clinical cancer imaging.

Many cancers upregulate transmembrane monocarboxylate transporters (MCTs) as a mechanism to prevent apoptosis due to the accumulation of lactate and decreased pH from aerobic glycolytic pathways, and hence are a target of interest for imaging. A fluorinated analog of α-cyano-4-hydroxycinnamic acid ((E)-2-cyano-3-{4-[(3-[¹⁸F]fluroropropyl)(propyl)amino]-2-methoxyphenyl}acrylic acid), called fluorine-18 (¹⁸F)-FACH herein, was developed by the authors for molecular imaging. Sattler et al set out to assess the radiation exposure and pharmacokinetics of the ¹⁸F-FACH radioligand in young pigs.

Pigs were given an intravenous administration of 156 MBq ± 54 (0.63 μg ± 0.49) of ¹⁸F-FACH and were imaged sequentially over 4 hours with PET/CT. No adverse effects were observed in pigs upon monitoring vital signs. Various organs, including the liver, brain, kidneys, and urinary bladder, were analyzed by using whole-body CT scans to determine the time-integrated activity concentrations of ¹⁸F-FACH. With the use of acquired imaging data, the effective dose (ED) was determined for clinical translation.

The highest contributors to the ED were the urinary bladder, red marrow, stomach, right colon, lungs, and the liver. They found that the ED of ¹⁸F-FACH was about 12.4 μSv/MBq in swine and, using prior translational dose estimates and conversion factors, determined that the ED for human use would be approximately 20.6 μSv/MBq of administered ¹⁸F-FACH. Together, a standard injection of 300 MBq in a human would result in an ED of 6.2 mSv. Taken together, the developed ¹⁸F-FACH radioligand was safe in the preclinical swine model, and further testing of target specificity is warranted for clinical imaging translation.

Highlighted Article

• Sattler B, Kranz M, Wenzel B, et al. Preclinical incorporation dosimetry of [¹⁸F]FACH—a novel ¹⁸F-labeled MCT1/MCT4 lactate transporter inhibitor for imaging cancer metabolism with PET. Molecules 2020;25(9):2424. doi: https://doi.org/10.3390/molecules25092024