First Evaluation of PET-Based Human Biodistribution and Dosimetry of ¹⁸F-FAZA, a Tracer for Imaging Tumor Hypoxia

Abstract

18 F-labeled fluoroazomycinarabinoside ( 18 F-FAZA) is a PET biomarker for noninvasive identification of regional tumor hypoxia. The aim of the present phase I study was to evaluate the biodistribution and dosimetry of 18 F-FAZA in non-small cell lung cancer patients. Methods: Five patients awaiting surgical resection of histologically proven or radiologically suspected non-small cell lung cancer were prospectively enrolled in the study. The patients underwent PET/CT after injection of 371 6 32 MBq of 18 F-FAZA. The protocol consisted of a 10-min dynamic acquisition of the heart to calculate the activity in blood, followed by 4 whole-body PET/CT scans, from the vertex to the mid thigh, at 10, 60, 120, and 240 min after injection. Urine samples were collected after each imaging session and at 360 min after injection. Volumes of interest were drawn around visually identifiable source organs to generate time-activity curves. Residence times were determined from time-activity curves, and effective doses to individual organs and the whole body were calculated using OLINDA/EXM 1.2 for the standard male and female phantoms. Results: Blood clearance was characterized by a rapid distribution followed by first-order elimination. The highest uptake was in muscle and liver, with respective percentage injected activity (%IA) peaks of 42.7 6 5.3 %IA and 5.5 6 0.6 %IA. The total urinary excretion was 15 %IA. The critical organ, with the highest absorbed radiation doses, was the urinary bladder wall, at 0.047 6 0.008 and 0.067 6 0.007 mGy/ MBq for the 2-and 4-h voiding intervals, respectively. The effective doses for the standard male and female phantoms were 0.013 6 0.004 and 0.014 6 0.004 mSv/MBq, respectively, depending on the voiding schedule. Conclusion: With respect to the available literature, the biodistribution of 18 F-FAZA in humans appeared to be slightly different from that in mice, with a low clearance in humans. Therefore, use of animal data may moderately underestimate radiation doses to organs in humans. Our dosimetry data showed that a 370-MBq injection of 18 F-FAZA is safe for clinical use, similar to other widely used PET ligands. In particular, the effective dose is not appreciably different from those obtained with other hypoxia tracers, such as 18 F-fluoromisonidazole.

Oxygen Sensing, Hypoxia Tracing and in Vivo Imaging with Functional Metalloprobes for the Early Detection of Non-communicable Diseases

“…The improved hydrophilicity allows for faster clearance from normoxic tissues and a better imaging contrast at earlier time points than FMISO as demonstrated in breast (EMT6) and pancreatic cancer (AR42J) tumors in mice models (Piert et al, 2005 ). Biodistribution studies revealed differences in humans compared to animals where slower clearance from kidneys in humans was observed although still rendered a favorable radiation risk profile for applications in PET imaging (Savi et al, 2017 ). Successful clinical studies have been carried out in glioma (Postema et al, 2009 ), lymphoma (Postema et al, 2009 ), lung (Postema et al, 2009 ; Bollineni et al, 2013 ), head and neck (Grosu et al, 2007 ) or cervical cancers (Schuetz et al, 2010 ).…”

Biodistribution and radiation dosimetry of the novel hypoxia PET probe [18F]DiFA and comparison with [18F]FMISO

“…[ 18 F]DiFA had a higher rate of urinary excretion (86.4%) than other hypoxia tracers, such as [ 18 F]FAZA (15% [11]), [ 18 F]FETNIM (60% [15]), and [ 18 F]HX4 (45% at 3.6 h [14]). In general, more hydrophilic compounds will have more rapid biodistribution and clearance from the body [16].…”

“…3.1 (PMOD Technologies, Zurich, Switzerland). The uptake of each major organ was calculated by drawing a volume of the region based on the contours of the PET and CT images as described previously [11]. At each time point, the decayed radioactivity of each source organ is expressed as a percentage of the injected activity (%IA) and plotted against time, and fitted to an exponential or sum-of-exponentials function in organ level internal dose assessment/exponential modeling (OLINDA/EXM) 1.1 computer software (Vanderbilt University, Nashville, TN) [12] to determine the total number of disintegrations per unit of administered activity, hereafter referred to as the normalized number of disintegrations.…”

“…Urine samples were collected for the following intervals: 0–1 h, 1–2 h, 2–4 h, 4–6 h, 6–9 h, and 9–24 h. The urine samples were assayed for radioactivity with an auto-well gamma counter (ARC-400; Hitachi, Tokyo) to estimate the total excreted activity. The residence time of the urinary bladder was also determined using the dynamic bladder model in OLINDA/EXM 1.1 as described previously [11].…”

Hypoxia imaging and theranostic potential of [64Cu][Cu(ATSM)] and ionic Cu(II) salts: a review of current evidence and discussion of the retention mechanisms

“…In contrast, detection of tumor hypoxia in PET is a direct measurement, presenting higher sensitivity and is directly quantitative. Compared to the more commonly used fluorine-based PET tracers, tracers based on copper allow a rapid visualization of hypoxia (in contrast to [ 18 F]F-MISO), or better penetration of the blood-brain barrier and no urinary bladder uptake (in contrast to [ 18 F]FAZA) [11,12], in addition to longer half-lives that contributes to better image quality and more convenient clinical practice. Here, we focus on reviewing recent advances and challenges in imaging of tumor hypoxia using PET with one of the most promising copper tracers, [ 64 Cu][Cu-diacetyl-bis(N 4methylthiosemicarbazone)] ([ 64 Cu][Cu(ATSM)]), and simple ionic [ 64 Cu]Cu(II) salts, as well as implications on using these tracers for simultaneous internal molecular radiotherapy.…”