Nonclinical investigations of a novel heart-type fatty acid-binding protein ligand, [18F]LUF: three-lot process validation, safety assessment, and radiation dosimetry.

BACKGROUND

Heart-type fatty acid-binding protein (FABP3) mediates the intracellular transport of fatty acids and is highly expressed in the myocardium. During myocardial infarction, FABP3 leaks from the myocardial cytoplasm into the blood; thus, detection of FABP3 using positron emission tomography (PET) is useful in identifying the site of myocardial damage. 4-(4-Fluoro-2-(1-phenyl-5-(2-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)phenoxy)butanoic acid (LUF) is a small-molecule organic compound that specifically binds FABP3. We confirmed that fluorine-18-labeled LUF enables clear, high-quality visualization of the myocardium as well as lesions associated with myocardial injury. In this study, we performed a process validation of [18F]LUF production for clinical use and evaluated its nonclinical toxicity and radiation dosimetry estimates using mouse biodistribution data.

RESULTS

The activity yield of [18F]LUF at the end of synthesis was > 8 GBq, with > 99% radiochemical purity, > 500 GBq/μmol molar activity, and < 1.5 μg/185 MBq total chemical content. All process validation batches complied with the product specifications. An extended single-dose intravenous toxicity study in male and female Sprague-Dawley rats indicated a no-observed adverse effect level for LUF and decay-outed [18F]LUF injection solution of ≥ 25 μg/kg and ≥ 2.5 mL/kg, respectively. These doses are > 100 times the postulated maximum dose of LUF (0.25 μg/kg) and [18F]LUF injection solution (370 MBq). Reverse mutation tests were negative for LUF and the OH form produced after β-decay of [18F]LUF. Neither LUF nor the OH form exhibited cardiotoxicity toward cardiomyocytes derived from human induced pluripotent stem cells at > 100 times the postulated maximum dose. Biodistribution study results demonstrated predominantly hepatobiliary excretion of radioactivity. The most critical organ affected was the heart wall (68.6 μGy/MBq). The estimated effective dose was calculated as 10.2 μSv/MBq. These radiation exposure doses are equivalent to 25.4 mGy (heart wall) and 3.78 mSv for a planned maximum dose of 370 MBq.

CONCLUSIONS

[18F]LUF shows acceptable pharmacological safety at the dose required for adequate PET imaging. The potential risks associated with [18F]LUF injection are well within the acceptable dose limits.