Initial Preclinical Evaluation of <sup>18</sup>F-Fluorodeoxysorbitol PET as a Novel Functional Renal Imaging Agent

Wakabayashi, Hiroshi; Werner, Rudolf A.; Hayakawa, Nobuyuki; Javadi, Mehrbod S.; Chen, Xinyu; Herrmann, Ken; Rowe, Steven P.; Lapa, Constantin; Higuchi, Takahiro

doi:10.2967/jnumed.116.172718

Cited by 27 publications

(18 citation statements)

References 17 publications

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“…In addition, 18 F-FDS PET also demonstrated a PET signal proportionate to the bacterial burden with the ability to monitor therapeutic failures associated with ESBL-producing E. coli (clinical isolates) infections in real-time (4). Recently, 18 F-FDS was shown to have high renal excretion, low plasma protein binding and high metabolic stability in rats (29). In a study of healthy volunteers, 18 F-FDS was determined to be safe, well-tolerated, and rapidly cleared, following a single, intravenous dose (30), suggesting promising potential for use in humans.…”

Section: Discussionmentioning

confidence: 99%

A Systematic Approach for Developing Bacteria-Specific Imaging Tracers

et al. 2016

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The modern patient is increasingly susceptible to bacterial infections including those due to multi-drug resistant organisms (MDROs). Noninvasive whole-body analysis with pathogen-specific imaging technologies can significantly improve patient outcomes by rapidly identifying a source of infection and monitoring the response to treatment, but no such technology exists clinically. Methods We systematically screened 961 random, radiolabeled molecules in silico as substrates for essential metabolic pathways in bacteria, followed by in vitro uptake in representative bacteria – Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and mycobacteria. Fluorine-labeled analogs, that could be developed as positron emission tomography (PET)-based imaging tracers, were evaluated in a murine myositis model. Results We identified three novel, non-toxic molecules demonstrating selective bacterial uptake: para-aminobenzoic acid (PABA), with uptake in all representative bacteria including Mycobacterium tuberculosis; mannitol, with selectively uptake in S. aureus and E. coli; and sorbitol, accumulating only in E. coli. None accumulated in mammalian cells or heat-killed bacteria, suggesting metabolism-derived specificity. In addition to an extended bacterial panel of laboratory strains, all three molecules rapidly accumulated in respective clinical isolates of interest including MDROs such as methicillin resistant S. aureus (MRSA), extended-spectrum beta-lactamase (ESBL)-producing, and carbapenem-resistant Enterobacteriaceae. In a murine myositis model, fluorine-labeled analogs of all three molecules could rapidly detect and differentiate infection sites from sterile inflammation in mice (P=0.03). Finally, 2-deoxy-2-[F-18]fluoro-D-sorbitol (18F-FDS) can be easily synthesized from 2-deoxy-2-[F-18]fluoro-D-glucose (18F-FDG). PET, utilizing 18F-FDS synthesized using current good manufacturing practice, could rapidly differentiate true infection from sterile inflammation to selectively localize E. coli infection in mice. Conclusion We have developed a systematic approach that exploits unique biochemical pathways in bacteria to develop novel pathogen-specific imaging tracers. These tracers have significant potential for clinical translation to specifically detect and localize a broad range of bacteria, including MDROs.

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Section: Discussionmentioning

confidence: 99%

A Systematic Approach for Developing Bacteria-Specific Imaging Tracers

et al. 2016

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“…All reconstructed images were corrected for 18 F decay, random coincidences, and dead time. A 13 min transmission scan was also conducted prior to the emission scan for attenuation correction 17 .…”

Section: Methodsmentioning

confidence: 99%

Left Ventricular Diastolic Dysfunction in a Rat Model of Diabetic Cardiomyopathy using ECG-gated 18F-FDG PET

Werner

Eissler

Hayakawa

et al. 2018

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In diabetic cardiomyopathy, left ventricular (LV) diastolic dysfunction is one of the earliest signs of cardiac involvement prior to the definitive development of heart failure (HF). We aimed to explore the LV diastolic function using electrocardiography (ECG)-gated 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging beyond the assessment of cardiac glucose utilization in a diabetic rat model. ECG-gated 18F-FDG PET imaging was performed in a rat model of type 2 diabetes (ZDF fa/fa) and ZL control rats at age of 13 weeks (n = 6, respectively). Under hyperinsulinemic-euglycemic clamp to enhance cardiac activity, 18F-FDG was administered and subsequently, list-mode imaging using a dedicated small animal PET system with ECG signal recording was performed. List-mode data were sorted and reconstructed into tomographic images of 16 frames per cardiac cycle. Left ventricular functional parameters (systolic: LV ejection fraction (EF), heart rate (HR) vs. diastolic: peak filling rate (PFR)) were obtained using an automatic ventricular edge detection software. No significant difference in systolic function could be obtained (ZL controls vs. ZDF rats: LVEF, 62.5 ± 4.2 vs. 59.4 ± 4.5%; HR: 331 ± 35 vs. 309 ± 24 bpm; n.s., respectively). On the contrary, ECG-gated PET imaging showed a mild but significant decrease of PFR in the diabetic rats (ZL controls vs. ZDF rats: 12.1 ± 0.8 vs. 10.2 ± 1 Enddiastolic Volume/sec, P < 0.01). Investigating a diabetic rat model, ECG-gated 18F-FDG PET imaging detected LV diastolic dysfunction while systolic function was still preserved. This might open avenues for an early detection of HF onset in high-risk type 2 diabetes before cardiac symptoms become apparent.

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“…Given these benefits, several PET radiotracers have been evaluated for renal imaging with promising results (2,7). With the benefits of a longer radiological half-life, 18 F-FDS has also been recently evaluated as a potential renal imaging agent (as a replacement for 99m Tc-DTPA) in healthy and diseased rats as well as healthy human subjects (24)(25)(26). Compared to 99m Tc-DTPA, the tubular function reflecting radiotracer 99m Tc-MAG3 has a more efficient extraction fraction (twice that of 99m Tc-DTPA), which renders it as the preferred imaging agent in patients with suspected obstruction and impaired renal function (27).…”

Section: Spatiotemporal Resolution and Renal Kinetics Of 11 C-paba Inmentioning

confidence: 99%

¹¹C-PABA as a PET Radiotracer for Functional Renal Imaging: Preclinical and First-in-Human Study

et al. 2020

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para-Aminobenzoic acid (PABA) has been previously used as an exogenous marker to verify completion of 24-hour urine sampling. Therefore, we hypothesized that radiolabeled PABA with 11 C could allow high-quality dynamic PET of the kidneys while reducing the radiation exposure due to its short biological and physical half-lives. We evaluated if 11 C-PABA could visualize renal anatomy and quantify function in healthy rats, rabbits, and first-inhuman studies in healthy volunteers. Methods: Healthy rats and rabbits were injected with 11 C-PABA intravenously. Subsequently, a dynamic PET was performed followed by post-mortem tissue biodistribution studies. 11 C-PABA PET was directly compared with the current standard, 99m Tc-MAG3 in rats. Three healthy human subjects also underwent dynamic PET after intravenous injection of 11 C-PABA. Results: In healthy rats and rabbits, dynamic PET demonstrated a rapid accumulation of 11 C-PABA in the renal cortex, followed by rapid excretion through the pelvicalyceal system. In humans, 11 C-PABA PET was safe and well tolerated. There were no adverse or clinically detectable pharmacologic effects in any subject. The cortex was delineated on PET, and the activity gradually transited to the medulla and then renal pelvis with high spatiotemporal resolution. Conclusion: 11 C-PABA demonstrated fast renal excretion with very low background signal in animals and humans. These results suggest that 11 C-PABA could be used as a novel radiotracer for functional renal imaging, providing high-quality spatiotemporal images with low radiation exposure.

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Initial Preclinical Evaluation of ¹⁸F-Fluorodeoxysorbitol PET as a Novel Functional Renal Imaging Agent

Cited by 27 publications

References 17 publications

A Systematic Approach for Developing Bacteria-Specific Imaging Tracers

A Systematic Approach for Developing Bacteria-Specific Imaging Tracers

Left Ventricular Diastolic Dysfunction in a Rat Model of Diabetic Cardiomyopathy using ECG-gated 18F-FDG PET

¹¹C-PABA as a PET Radiotracer for Functional Renal Imaging: Preclinical and First-in-Human Study

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Initial Preclinical Evaluation of 18F-Fluorodeoxysorbitol PET as a Novel Functional Renal Imaging Agent

Cited by 27 publications

References 17 publications

A Systematic Approach for Developing Bacteria-Specific Imaging Tracers

A Systematic Approach for Developing Bacteria-Specific Imaging Tracers

Left Ventricular Diastolic Dysfunction in a Rat Model of Diabetic Cardiomyopathy using ECG-gated 18F-FDG PET

11C-PABA as a PET Radiotracer for Functional Renal Imaging: Preclinical and First-in-Human Study

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Initial Preclinical Evaluation of ¹⁸F-Fluorodeoxysorbitol PET as a Novel Functional Renal Imaging Agent

¹¹C-PABA as a PET Radiotracer for Functional Renal Imaging: Preclinical and First-in-Human Study