Safety, pharmacokinetics, metabolism and radiation dosimetry of 18F-tetrafluoroborate (18F-TFB) in healthy human subjects

EJNMMI Research, Oct 2017

Background 18F-Tetrafluoroborate (18F-TFB) is a promising iodide analog for PET imaging of thyroid cancer and sodium/iodide symporter (NIS) reporter activity in viral therapy applications. The aim of this study was to evaluate the safety, pharmacokinetics, biodistribution, and radiation dosimetry of high-specific activity 18F-TFB in healthy human subjects. Methods 18F-TFB was synthesized with specific activity of 3.2 ± 1.3 GBq/μmol (at the end of synthesis). Dynamic and whole-body static PET/CT scans over 4 h were performed after intravenous administration of 18F-TFB (333–407 MBq) in four female and four male healthy volunteers (35 ± 11 years old). Samples of venous blood and urine were collected over the imaging period and analyzed by ion-chromatography HPLC to determine tracer stability. Vital signs and clinical laboratory safety assays were measured to evaluate safety. Results 18F-TFB administration was well tolerated with no significant findings on vital signs and no clinically meaningful changes in clinical laboratory assays. Left-ventricular blood pool time-activity curves showed a multi-phasic blood clearance of 18F-radioactivity with the two rapid clearance phases over the first 20 min, followed by a slower clearance phase. HPLC analysis showed insignificant 18F-labeled metabolites in the blood and urine over the length of the study (4 h). High uptakes were seen in the thyroid, stomach, salivary glands, and bladder. Urinary clearance of 18F-TFB was prominent. Metabolic stability was evidenced by low accumulation of 18F-radioactivity in the bone. Effective doses were 0.036 mSv/MBq in males and 0.064 mSv/MBq in females (p = 0.08, not significant). Conclusions This initial study in healthy human subjects showed 18F-TFB was safe and distributed in the human body similar to other iodide analogs. These data support further translational studies with 18F-TFB as NIS gene reporter and imaging biomarker for thyroid cancer and other disease processes that import iodide.

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Safety, pharmacokinetics, metabolism and radiation dosimetry of 18F-tetrafluoroborate (18F-TFB) in healthy human subjects

Jiang et al. EJNMMI Research Safety, pharmacokinetics, metabolism and 18 radiation dosimetry of F-tetrafluoroborate 18 ( F-TFB) in healthy human subjects Huailei Jiang 2 Nicholas R. Schmit 2 Alex R. Koenen 2 Aditya Bansal 2 Mukesh K. Pandey 2 Robert B. Glynn 2 Bradley J. Kemp 2 Kera L. Delaney 2 Angela Dispenzieri 1 Jamie N. Bakkum-Gamez 0 Kah-Whye Peng 4 Stephen J. Russell 4 Tina M. Gunderson 3 Val J. Lowe 2 Timothy R. DeGrado 2 0 Department of Obstetrics and Gynecology, Mayo Clinic , Rochester, MN , USA 1 Department of Medicine, Mayo Clinic , Rochester, MN , USA 2 Department of Radiology, Mayo Clinic , 200 First St. SW, Rochester, MN 55905 , USA 3 Department of Clinical Statistics, Mayo Clinic , Rochester, MN , USA 4 Department of Molecular Medicine, Mayo Clinic , Rochester, MN , USA Background: 18F-Tetrafluoroborate (18F-TFB) is a promising iodide analog for PET imaging of thyroid cancer and sodium/iodide symporter (NIS) reporter activity in viral therapy applications. The aim of this study was to evaluate the safety, pharmacokinetics, biodistribution, and radiation dosimetry of high-specific activity 18F-TFB in healthy human subjects. Methods: 18F-TFB was synthesized with specific activity of 3.2 ± 1.3 GBq/μmol (at the end of synthesis). Dynamic and whole-body static PET/CT scans over 4 h were performed after intravenous administration of 18F-TFB (333407 MBq) in four female and four male healthy volunteers (35 ± 11 years old). Samples of venous blood and urine were collected over the imaging period and analyzed by ion-chromatography HPLC to determine tracer stability. Vital signs and clinical laboratory safety assays were measured to evaluate safety. Results: 18F-TFB administration was well tolerated with no significant findings on vital signs and no clinically meaningful changes in clinical laboratory assays. Left-ventricular blood pool time-activity curves showed a multiphasic blood clearance of 18F-radioactivity with the two rapid clearance phases over the first 20 min, followed by a slower clearance phase. HPLC analysis showed insignificant 18F-labeled metabolites in the blood and urine over the length of the study (4 h). High uptakes were seen in the thyroid, stomach, salivary glands, and bladder. Urinary clearance of 18F-TFB was prominent. Metabolic stability was evidenced by low accumulation of 18F-radioactivity in the bone. Effective doses were 0.036 mSv/MBq in males and 0.064 mSv/MBq in females (p = 0.08, not significant). Conclusions: This initial study in healthy human subjects showed 18F-TFB was safe and distributed in the human body similar to other iodide analogs. These data support further translational studies with 18F-TFB as NIS gene reporter and imaging biomarker for thyroid cancer and other disease processes that import iodide. Sodium/iodide symporter; Tetrafluoroborate; 18F-fluorine; PET imaging; Biodistribution; Dosimetry Background The sodium/iodide symporter (NIS) is an intrinsic membrane glycoprotein highly expressed in the thyroid gland and other NIS-expressing cells or tissues [ 1–3 ]. Human NIS (hNIS) was identified and characterized in 1996 [ 4, 5 ], which created various new opportunities using hNIS as a reporter gene in viral therapy investigations and imaging of cell migration and differentiation. Non-invasive monitoring of hNIS expression in normal and hNIS-transfected tissues has been performed by single-photon emission computed tomography (SPECT) with single-photon emitting radioiodides (123I and 125I) and 99mTc-pertechnetate (99mTc-TcO4−), whereas positron emission tomography (PET) has used 124I-iodide as radiotracer [6]. However, clinical implementation of an 18F-fluorine-based radiotracer in positron emission tomography (PET) has lagged, despite of its superior physical decay properties. 18F-tetrafluoroborate (18FTFB) has received renewed interest as a promising iodide analog radiotracer for PET imaging in preclinical imaging studies [ 7–10 ]. During preparation of this manuscript, the biodistribution and radiation dosimetry estimates of 18F-TFB in five thyroid cancer patients were reported [11]. Our laboratory [ 12 ] and others [ 13 ] have reported high-specific radioactivity syntheses of 18F-TFB via the reaction of boron trifluoride (BF3) and 18F-fluoride. We demonstrated the relationship of 18F-TFB-specific radioactivity and PET-delineated radiotracer uptake in NIS-transfected C6-glioma xenograft bearing mice [ 14 ], confirming the desirability of high-specific radioactivity to avoid saturation effects at the NIS transporter. In this study, we report PET/CT imaging with 18F-TFB in healthy male and female participants to describe radiotracer pharmacokinetics, metabolite analyses, and estimation of radiation dosimetry estimates. Methods Radiotracer synthesis 18F-TFB was prepared and formulated in sterile 0.9% NaCl under Current Good Manufacturing Practice (cGMP) conditions as previously described [ 12 ]. Decaycorrected radiochemical yields of (...truncated)


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Huailei Jiang, Nicholas R. Schmit, Alex R. Koenen, Aditya Bansal, Mukesh K. Pandey, Robert B. Glynn, Bradley J. Kemp, Kera L. Delaney, Angela Dispenzieri, Jamie N. Bakkum-Gamez, Kah-Whye Peng, Stephen J. Russell, Tina M. Gunderson, Val J. Lowe, Timothy R. DeGrado. Safety, pharmacokinetics, metabolism and radiation dosimetry of 18F-tetrafluoroborate (18F-TFB) in healthy human subjects, EJNMMI Research, 2017, pp. 90, Volume 7, Issue 1, DOI: 10.1186/s13550-017-0337-5