Pharmacokinetics, Metabolism, Biodistribution, Radiation Dosimetry, and Toxicology of 18F-Fluoroacetate (18F-FACE) in Non-human Primates

Abstract

Introduction To facilitate the clinical translation of 18F-fluoroacetate (18F-FACE), the pharmacokinetics, biodistribution, radiolabeled metabolites, radiation dosimetry, and pharmacological safety of diagnostic doses of 18F-FACE were determined in non-human primates. Methods 18F-FACE was synthesized using a custom-built automated synthesis module. Six rhesus monkeys (three of each sex) were injected intravenously with 18F-FACE (165.4± 28.5 MBq), followed by dynamic positron emission tomography (PET) imaging of the thoracoabdominal area during 0–30 min post-injection and static whole-body PET imaging at 40, 100, and 170 min. Serial blood samples and a urine sample were obtained from each animal to determine the time course of 18F-FACE and its radiolabeled metabolites. Electrocardiograms and hematology analyses were obtained to evaluate the acute and delayed toxicity of diagnostic dosages of 18F-FACE. The time-integrated activity coefficients for individual source organs and the whole body after administration of 18F-FACE were obtained using quantitative analyses of dynamic and static PET images and were extrapolated to humans. Results The blood clearance of 18F-FACE exhibited bi-exponential kinetics with half-times of 4 and 250 min for the fast and slow phases, respectively. A rapid accumulation of 18F-FACE-derived radioactivity was observed in the liver and kidneys, followed by clearance of the radioactivity into the intestine and the urinary bladder. Radio-HPLC analyses of blood and urine samples demonstrated that 18F-fluoride was the only detectable radiolabeled metabolite at the level of less than 9% of total radioactivity in blood at 180 min after the 18F-FACE injection. The uptake of free 18F-fluoride in the bones was insignificant during the course of the imaging studies. No significant changes in ECG, CBC, liver enzymes, or renal function were observed. The estimated effective dose for an adult human is 3.90–7.81 mSv from the administration of 185–370 MBq of 18F-FACE. Conclusions The effective dose and individual organ radiation absorbed doses from administration of a diagnostic dosage of 18F-FACE are acceptable. From a pharmacologic perspective, diagnostic dosages of 18F-FACE are non-toxic in primates and, therefore, could be safely administered to human patients for PET imaging.

Imaging epigenetic regulation by histone deacetylases in the brain using PET/MRI with 18F-FAHA

“…The radiosynthesis of [ 18 F]FACE was performed as described by us previously (Nishii et al, 2011). Specific activity of [ 18 F]FACE was 1.162 Ci/µmole (43GBq/µmole).…”

Metabolism and Quantification of [18F]DPA-714, a New TSPO Positron Emission Tomography Radioligand

“…This compound is known to be further converted to [ 18 F]fluoride (Tecle and Casida, 1989;Marik et al, 2009;Ponde et al, 2007;Nishii et al, 2012). In previous imaging studies in rodents, the free [ (Fookes et al, 2008).…”

“…In baboons, the radioactivity uptake observed in vertebra was probably due both to specific uptake of radioactivity in the bone marrow and to the uptake of [ 18 F]fluoride in the bones. Different metabolic pathways and species differences have been described for [ 18 F]fluoroacetate (Nishii et al, 2012). The differences in the extent of defluorination of [ 18 F]-DPA-714 between species (Fookes et al, 2008;James et al, 2008;Arlicot et al, 2012) may be explained by a difference in the metabolism of the radioligand by O-deethylation and a difference in the metabolic pathways of fluoroacetate (Tecle and Casida, 1989).…”

Molecular Neuroimaging: The Basics

“…There are numerous other PET agents under development such as Fluoro-L-Thymidine (FLT) designed to serve as probes for DNA synthesis, and [18F]choline [31] and [18F]acetate [32] to target fatty acid metabolism.…”