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

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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.

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Acknowledgments

This work was supported by the NIH-NCI CA-016672 (MD Anderson Cancer Center Support Grant) and new project development funds of the Department of Experimental Diagnostic Imaging, MDACC. We thank Nancy Swanston, CNMT, for help with the PET studies, Karen Yoas for help in coordinating this study, and the anonymous reviewers for their insights and advice.

Conflict of Interest Disclosure

The authors declare that they have no conflict of interest.

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Author notes

  1. Ryuichi Nishii

    Present address: , Moriyama 5-4-30, Moriyama-shi, Shiga, 524-8524, Japan

  2. Luc Bidaut

    Present address: Centre for Oncology & Molecular Medicine, Ninewells Hospital and Medical School, University of Dundee, James Arrott Drive, Dundee, DD1 9SY, Scotland, UK

Authors and Affiliations

  1. Department of Experimental Diagnostic Imaging, Center for Advanced Biomedical Imaging Research (CABIR), UT M. D. Anderson Cancer Center, 1881 East Road 3SCR2.3924, Houston, TX, 77054, USA

    Ryuichi Nishii, William Tong, Suren Soghomonyan, Uday Mukhopadhyay, Julius Balatoni, Mian Alauddin, Carlos Gonzalez-Lepera, Bijun Yang & Juri G. Gelovani

  2. Department of Imaging Physics, UT M. D. Anderson Cancer Center, Houston, TX, USA

    Richard Wendt III, Osama Mawlawi & Luc Bidaut

  3. Department of Veterinary Medicine & Surgery, UT M. D. Anderson Cancer Center, Houston, TX, USA

    Peggy Tinkey & Agatha Borne

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  1. Ryuichi Nishii
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Correspondence to Juri G. Gelovani.

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Ryuichi Nishii and William Tong contributed equally to this work.

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Nishii, R., Tong, W., Wendt, R. et al. Pharmacokinetics, Metabolism, Biodistribution, Radiation Dosimetry, and Toxicology of 18F-Fluoroacetate (18F-FACE) in Non-human Primates. Mol Imaging Biol 14, 213–224 (2012). https://doi.org/10.1007/s11307-011-0485-3

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