Pharmacokinetics, metabolism, biodistribution, radiation dosimetry, and toxicology of 18F-fluoroacetate ( 18F-FACE) in non-human primates

Nishii, Ryuichi, Tong, William, Wendt III, Richard, Soghomonyan, Suren, Mukhopadhyay, Uday, Balatoni, Julius, Mawlawi, Osama, Bidaut, Luc, Tinkey, Peggy, Borne, Agatha, Alauddin, Mian, Gonzalez-LeperaBijun, Carlos, Yang, Bijun and YangJuri, G. (2012) Pharmacokinetics, metabolism, biodistribution, radiation dosimetry, and toxicology of 18F-fluoroacetate ( 18F-FACE) in non-human primates. Molecular Imaging and Biology, 14 (2). pp. 213-224. ISSN 1536-1632

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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. © Academy of Molecular Imaging and Society for Molecular Imaging, 2011.

Keywords:fluorine 18, fluoroacetic acid f 18, radiopharmaceutical agent, unclassified drug, acute toxicity, animal experiment, article, blood sampling, controlled study, diagnostic imaging, dosimetry, drug absorption, drug accumulation, drug clearance, drug distribution, drug half life, drug metabolism, drug synthesis, drug uptake, electrocardiogram, female, high performance liquid chromatography, image analysis, image display, male, nonhuman, plasma clearance, positron emission tomography, priority journal, quantitative analysis, radiation dose distribution, radioactivity, rhesus monkey, toxicity testing, urinalysis, whole body imaging, Animals, Chromatography, High Pressure Liquid, Electrocardiography, Fluorine Radioisotopes, Fluoroacetates, Humans, Injections, Intravenous, Macaca mulatta, Organ Specificity, Positron-Emission Tomography and Computed Tomography, Radiometry, Time Factors, Tissue Distribution, Toxicity Tests, Acute, Animalia, Primates
Subjects:F Physical Sciences > F350 Medical Physics
Divisions:College of Science > School of Computer Science
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ID Code:24124
Deposited On:30 Oct 2016 11:52

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