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

To facilitate the clinical translation of F-18-fluoroacetate (F-18-FACE), the pharmacokinetics, biodistribution, radiolabeled metabolites, radiation dosimetry, and pharmacological safety of diagnostic doses of F-18-FACE were determined in non-human primates.

F-18-FACE was synthesized using a custom-built automated synthesis module. Six rhesus monkeys (three of each sex) were injected intravenously with F-18-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 F-18-FACE and its radiolabeled metabolites. Electrocardiograms and hematology analyses were obtained to evaluate the acute and delayed toxicity of diagnostic dosages of F-18-FACE. The time-integrated activity coefficients for individual source organs and the whole body after administration of F-18-FACE were obtained using quantitative analyses of dynamic and static PET images and were extrapolated to humans.

The blood clearance of F-18-FACE exhibited bi-exponential kinetics with half-times of 4 and 250 min for the fast and slow phases, respectively. A rapid accumulation of F-18-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 F-18-fluoride was the only detectable radiolabeled metabolite at the level of less than 9% of total radioactivity in blood at 180 min after the F-18-FACE injection. The uptake of free F-18-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 F-18-FACE.

The effective dose and individual organ radiation absorbed doses from administration of a diagnostic dosage of F-18-FACE are acceptable. From a pharmacologic perspective, diagnostic dosages of F-18-FACE are non-toxic in primates and, therefore, could be safely administered to human patients for PET imaging.