Biodistribution and radiation dosimetry of the hypoxia marker 18F–HX4 in monkeys and humans determined by using whole-body PET/CT

Doss, Mohan; Zhang, James J.; Belanger, Marie-Jose; Stubbs, James B.; Hostetler, Eric D.; Alpaugh, R. Katherine; Kolb, Hartmuth C.; Yu, Jinpu

doi:10.1097/mnm.0b013e3283407950

Cited by 47 publications

(35 citation statements)

References 15 publications

(16 reference statements)

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“…[ 18 F]HX4 biodistribution in normal tissues was found to be fast and homogeneous, as has already been published for [ 18 (16). This is, however, not surprising, because the highest [ 18 F]HX4 uptake was found in the urinary bladder, confirming excretion primarily through the kidneys.…”

Section: Discussionsupporting

confidence: 80%

“…This is, however, not surprising, because the highest [ 18 F]HX4 uptake was found in the urinary bladder, confirming excretion primarily through the kidneys. To reduce bladder and kidney dose, patients should therefore be encouraged to maintain adequate hydration and void frequently (15,16).…”

Section: Discussionmentioning

confidence: 99%

“…It represents a novel, click chemistry-based generation of derivatives in which structure-activity relationships, focused on the incorporation of a 1,2,3-triazole moiety, have been used to design an agent with preferred pharmacokinetic and clearance properties (15). Biodistribution and dosimetry studies in healthy monkeys and humans showed that the amount of unmetabolized [ 18 F]HX4 in blood and urine samples remained stable, liver and gastrointestinal tract uptake was relatively low, and the highest uptake of [ 18 F]HX4 was found in the urinary bladder, indicating an excretion primarily through the kidneys (15,16). Because of the better water solubility and faster clearance, we hypothesized that 18 F activity, as previously shown (11).…”

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confidence: 99%

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Preclinical evaluation and validation of [ ¹⁸ F]HX4, a promising hypoxia marker for PET imaging

Dubois

Lieuwes

Janssen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Hypoxia has been shown to be an important microenvironmental parameter influencing tumor progression and treatment efficacy. Patient guidance for hypoxia-targeted therapy requires evaluation of tumor oxygenation, preferably in a noninvasive manner. The aim of this study was to evaluate and validate the uptake of [ 18 F] HX4, a novel developed hypoxia marker for PET imaging. A heterogeneous accumulation of [ 18 F]HX4 was found within rat rhabdomyosarcoma tumors that was significantly (P < 0.0001) higher compared with the surrounding tissues, with temporal increasing tumor-to-blood ratios reaching a plateau of 7.638 ± 0.926 and optimal imaging properties 4 h after injection. [ 18 F]HX4 retention in normal tissues was found to be short-lived, homogeneous and characterized by a fast progressive temporal clearance. Heterogeneity in [ 18 F]HX4 tumor uptake was analyzed based on 16 regions within the tumor according to the different orthogonal planes at the largest diameter. Validation of heterogeneous [ 18 F]HX4 tumor uptake was shown by a strong and significant relationship (r = 0.722; P < 0.0001) with the hypoxic fraction as calculated by the percentage pimonidazole-positive pixels. Furthermore, a causal relationship with tumor oxygenation was established, because combination treatment of nicotinamide and carbogen resulted in a 40% reduction (P < 0.001) in [ 18 F]HX4 tumor accumulation whereas treatment with 7% oxygen breathing resulted in a 30% increased uptake (P < 0.05). [ 18 F]HX4 is therefore a promising candidate for noninvasive detection and evaluation of tumor hypoxia at a macroscopic level.cancer | nuclear medicine | experimental research T he presence of hypoxic regions due to abnormalities in tumor vasculature, heterogeneously spread within solid tumors influences clinical outcome; as it is an independent predictor of poor prognosis-free survival in several types of cancer (1). In contrast, this unique tumor characteristic makes it an attractive target for novel drugs to increase the therapeutic effect of conventional cancer treatment modalities. Another approach is the use of intensity-modulated radiotherapy to give a higher dose to hypoxic areas while sparing the surrounding normal tissue (2, 3). Although treatments to counteract the negative effect of intratumoral hypoxia are under investigation, not all patients will benefit from such selective treatments. Therefore, to guide hypoxiadirected therapies in individual patients, it is important to evaluate tumor oxygenation using a reliable noninvasive method.To date, a variety of methods are available for assessment of tumor oxygenation in solid tumors, of which polarographic oxygen electrodes and immunohistological assays remain the gold standard (4). These standard invasive modalities have not yielded reliable 3D images of the whole tumor for clinical use, and therefore research has been focused on noninvasive imaging techniques, such as positron-emission tomography (PET) using nitroimidazoles. The 2-nitroimidazole derivative fluoromisonidazole (FMISO)...

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Preclinical evaluation and validation of [ ¹⁸ F]HX4, a promising hypoxia marker for PET imaging

Dubois

Lieuwes

Janssen

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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123

122

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“…Despite being similar physiology to humans, human effective dose using monkey data could be either underestimated or overestimated. For example, the effective dose of hypoxia marker 18 F-HX4 estimated from monkey study is significantly higher (42 µSv/MBq) than the results obtained from humans (27 µSv/MBq) [30]. Moreover, although we do not expect that the anesthesia affects the biodistribution and metabolism of 64 Cu-BaBaSar-RGD 2 , it has been found that different anesthetic protocols can result a significant effect on the uptake of many organs [31].…”

Section: Discussionmentioning

confidence: 66%

Biodistribution and Radiation Dosimetry of the Integrin Marker 64Cu-BaBaSar-RGD2 Determined from Whole-Body PET/CT in a Non-human Primate

et al. 2017

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Introduction: 64 Cu-BaBaSar-RGD 2 is a positron emission radiotracer taken up by integrin α v β 3 , which is overexpressed in many malignancies. The aim of this study was to evaluate the biodistribution of 64 Cu-BaBaSar-RGD 2 in a non-human primate with positron emission tomography (PET) and to estimate the absorbed doses in major organs for human. Materials and Methods:Whole-body PET imaging was done on a Siemens Biograph scanner with a male macaque monkey. After an i.v. injection of 13.1-19.7 MBq/kg of 64 Cu-BaBaSar-RGD 2 , whole body scan was collected for a total duration of 180 min.Attenuation and scatter corrections were applied to reconstructions of the whole-body emission scan. After image reconstruction, three-dimensional volumes of interest (VOI) were hand-drawn on the PET transaxial or coronal slices of the frame where the organ was most conspicuous. Time-activity curves (TACs) for each VOI were obtained, and residence times of each organ were calculated by integration of the time-activity curves. Human absorbed doses were estimated using the standard human model in OLINDA/EXM software.Results: Injection of 64 Cu-BaBaSar-RGD 2 was well-tolerated in the macaque monkey, with no serious tracer-related adverse events observed. 64 Cu-BaBaSar-RGD 2 was cleared rapidly from the blood pool, with a 12.1-min biological half-life. Increased 64 CuBaBaSar-RGD 2 uptake was observed in the kidneys, and bladder, with mean percentage injected dose (ID%) values at 1 h after injection ∼35.50 ± 6.47 and 36.89 ± 5.48, respectively. The calculated effective dose was 15.30 ± 2.21 µSv/MBq, and the kidneys had the highest absorbed dose at 108.43 ± 16.41 µGy/MBq using the non-voiding model. For an injected activity of 925 MBq 64 Cu for human, the effective dose would be 14.2 ± 2.1 mSv.Discussion: Due to the limited availability of the primates, we evaluated 64 Cu-BaBaSar-RGD 2 in the same monkey using three imaging sessions. Measured absorbed doses and Liu et al.Radiation Dosimetry of 64 Cu-BaBaSar-RGD 2 Determined from Monkey effective doses of 64 Cu-BaBaSar-RGD 2 are comparable to other reported RGDderived radiopharmaceuticals labeled with 64 Cu and 18 F. Therefore, 64 Cu-BaBaSar-RGD 2 can be safely injected into humans for studying integrin α v β 3 expression non-invasively.

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“…18 F-FAZA imaging provides similar hypoxia information to 18 F-FMISO, which may be helpful for therapy planning [96]. In addition, Lehtiö et al [97] [103,104]. Cu(II)-ATSM, a neutral lipophilic molecule, is another alternative PET probe for hypoxia imaging based on a metal complex of radioactive copper with ATSM, diacetylbis(N4-methylthiosemicarbazone), which is highly membrane permeable.…”

Section: Hypoxia Pet Imagingmentioning

confidence: 99%

Current Molecular Imaging Positron Emitting Radiotracers in Oncology

Zhu

Shim

2011

Nucl Med Mol Imaging

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Molecular imaging is one of the fastest growing areas of medical imaging. Positron emission tomography (PET) has been widely used in the clinical management of patients with cancer. Nuclear imaging provides biological information at the cellular, subcellular, and molecular level in living subjects with noninvasive procedures. In particular, PET imaging takes advantage of traditional diagnostic imaging techniques and introduces positron-emitting probes to determine the expression of indicative molecular targets at different stages of cancer. 18 F-fluorodeoxyglucose ( 18 F-FDG), the only FDA approved oncological PET tracer, has been widely utilized in cancer diagnosis, staging, restaging, and even monitoring response to therapy; however, 18 F-FDG is not a tumor-specific PET tracer. Over the last decade, many promising tumor-specific PET tracers have been developed and evaluated in preclinical and clinical studies. This review provides an overview of the current non-18 F-FDG PET tracers in oncology that have been developed based on tumor characteristics such as increased metabolism, hyperproliferation, angiogenesis, hypoxia, apoptosis, and tumor-specific antigens and surface receptors.

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Biodistribution and radiation dosimetry of the hypoxia marker 18F–HX4 in monkeys and humans determined by using whole-body PET/CT

Cited by 47 publications

References 15 publications

Preclinical evaluation and validation of [ ¹⁸ F]HX4, a promising hypoxia marker for PET imaging

Preclinical evaluation and validation of [ ¹⁸ F]HX4, a promising hypoxia marker for PET imaging

Biodistribution and Radiation Dosimetry of the Integrin Marker 64Cu-BaBaSar-RGD2 Determined from Whole-Body PET/CT in a Non-human Primate

Current Molecular Imaging Positron Emitting Radiotracers in Oncology

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Biodistribution and radiation dosimetry of the hypoxia marker 18F–HX4 in monkeys and humans determined by using whole-body PET/CT

Cited by 47 publications

References 15 publications

Preclinical evaluation and validation of [ 18 F]HX4, a promising hypoxia marker for PET imaging

Preclinical evaluation and validation of [ 18 F]HX4, a promising hypoxia marker for PET imaging

Biodistribution and Radiation Dosimetry of the Integrin Marker 64Cu-BaBaSar-RGD2 Determined from Whole-Body PET/CT in a Non-human Primate

Current Molecular Imaging Positron Emitting Radiotracers in Oncology

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Preclinical evaluation and validation of [ ¹⁸ F]HX4, a promising hypoxia marker for PET imaging

Preclinical evaluation and validation of [ ¹⁸ F]HX4, a promising hypoxia marker for PET imaging