Assessing Glomerular Filtration in Small Animals Using [68Ga]DTPA and [68Ga]EDTA with PET Imaging

Gündel, Daniel; Pohle, Ulrike; Prell, Erik; Odparlik, Andreas; Thews, Oliver

doi:10.1007/s11307-017-1135-1

Cited by 12 publications

(10 citation statements)

References 24 publications

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“…Hence, the high plasma protein binding in vivo could at least explain the observed unspecific liver uptake in mice and piglets as shown in Figures 3B and 5C [33,34]. We suppose that its high albumin binding diminishes the excretion of intact [ 18 F]FACH via glomerular filtration, as recently described for [ 68 Ga]EDTA and [ 68 Ga]DTPA [35]. Indeed, other studies have shown that albumin binding reduces plasma clearance of the radiotracers in a speciesdependent manner [36,37].…”

Section: Discussionsupporting

confidence: 57%

Preclinical Evaluation of [18F]FACH in Healthy Mice and Piglets: An 18F-Labeled Ligand for Imaging of Monocarboxylate Transporters with PET

Gündel

Sadeghzadeh

Deuther‐Conrad

et al. 2021

IJMS

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The expression of monocarboxylate transporters (MCTs) is linked to pathophysiological changes in diseases, including cancer, such that MCTs could potentially serve as diagnostic markers or therapeutic targets. We recently developed [18F]FACH as a radiotracer for non-invasive molecular imaging of MCTs by positron emission tomography (PET). The aim of this study was to evaluate further the specificity, metabolic stability, and pharmacokinetics of [18F]FACH in healthy mice and piglets. We measured the [18F]FACH plasma protein binding fractions in mice and piglets and the specific binding in cryosections of murine kidney and lung. The biodistribution of [18F]FACH was evaluated by tissue sampling ex vivo and by dynamic PET/MRI in vivo, with and without pre-treatment by the MCT inhibitor α-CCA-Na or the reference compound, FACH-Na. Additionally, we performed compartmental modelling of the PET signal in kidney cortex and liver. Saturation binding studies in kidney cortex cryosections indicated a KD of 118 ± 12 nM and Bmax of 6.0 pmol/mg wet weight. The specificity of [18F]FACH uptake in the kidney cortex was confirmed in vivo by reductions in AUC0–60min after pre-treatment with α-CCA-Na in mice (−47%) and in piglets (−66%). [18F]FACH was metabolically stable in mouse, but polar radio-metabolites were present in plasma and tissues of piglets. The [18F]FACH binding potential (BPND) in the kidney cortex was approximately 1.3 in mice. The MCT1 specificity of [18F]FACH uptake was confirmed by displacement studies in 4T1 cells. [18F]FACH has suitable properties for the detection of the MCTs in kidney, and thus has potential as a molecular imaging tool for MCT-related pathologies, which should next be assessed in relevant disease models.

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Section: Discussionsupporting

confidence: 57%

Preclinical Evaluation of [18F]FACH in Healthy Mice and Piglets: An 18F-Labeled Ligand for Imaging of Monocarboxylate Transporters with PET

Gündel

Sadeghzadeh

Deuther‐Conrad

et al. 2021

IJMS

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“…Given that 99m Tc-labelled DTPA has been used for renal functional assessment over decades, Gundel et al [23] investigated the renal PET probe [ 68 Ga]DTPA in a head-to-head comparison with [ 68 Ga]EDTA in vitro and in vivo in male Copenhagen rats. Only 30% of the injected [ 68 Ga]DTPA activity was excreted via the kidneys (in contrast to almost 90% of [ 68 Ga]EDTA activity).…”

Section: Ga-labelled Radiotracers For Renal Function Imagingmentioning

confidence: 99%

“…Of note, compared to measured inulin clearance, [ 68 Ga]DTPA led to a marked underestimation of GFR by up to 80%. These findings are most likely explained by the strong binding of this radiotracer to plasma proteins [23]. Thus, compared to [ 68 Ga]DTPA, [ 68 Ga]EDTA demonstrates superior diagnostic performance in renal radionuclide PET imaging [6, 23].…”

Section: Ga-labelled Radiotracers For Renal Function Imagingmentioning

confidence: 99%

The next era of renal radionuclide imaging: novel PET radiotracers

Werner

Chen

Lapa

et al. 2019

Eur J Nucl Med Mol Imaging

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Although single-photon-emitting radiotracers have long been the standard for renal functional molecular imaging, recent years have seen the development of positron emission tomography (PET) agents for this application. We provide an overview of renal radionuclide PET radiotracers, in particular focusing on novel 18 F-labelled and 68 Ga-labelled agents. Several reported PET imaging probes allow assessment of glomerular filtration rate, such as [ 68 Ga]ethylenediaminetetraacetic acid ([ 68 Ga]EDTA), [ 68 Ga]IRDye800-tilmanocept and 2-deoxy-2-[ 18 F]fluorosorbitol ([ 18 F]FDS)). The diagnostic performance of [ 68 Ga]EDTA has already been demonstrated in a clinical trial. [ 68 Ga]IRDye800-tilmanocept shows receptor-mediated binding to glomerular mesangial cells, which in turn may allow the monitoring of progression of diabetic nephropathy. [ 18 F]FDS shows excellent kidney extraction and excretion in rats and, as has been shown in the first study in humans. Further, due to its simple one-step radiosynthesis via the most frequently used PET radiotracer 2-deoxy-2-[ 18 F]fluoro- d -glucose, [ 18 F]FDS could be available at nearly every PET centre. A new PET radiotracer has also been introduced for the effective assessment of plasma flow in the kidneys: Re(CO) 3 - N -([ 18 F]fluoroethyl)iminodiacetic acid (Re(CO) 3 ([ 18 F]FEDA)). This compound demonstrates similar pharmacokinetic properties to its 99m Tc-labelled analogue [ 99m Tc](CO) 3 (FEDA). Thus, if there is a shortage of molybdenum-99, Re(CO) 3 ([ 18 F]FEDA would allow direct comparison with previous studies with 99m Tc. The PET radiotracers for renal imaging reviewed here allow thorough evaluation of kidney function, with the tremendous advantage of precise anatomical coregistration with simultaneously acquired CT images and rapid three-dimensional imaging capability.

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“…Current tracers used in renal scan diagnostic imaging, such as diethylenetriaminepentaacetic acid (DTPA), mercapto-acetyl-triglycine (MAG3), dimercaptosuccinic acid (DMSA), and glucoheptonate (GHA) are radionuclide-chelates 3 - 9 that, depending on the main route of their renal-urinary clearance, each provides a slightly different advantage over the others to assess renal function or anatomy 10 , 11 . For instance, DTPA is primarily cleared by renal filtration and used in renal scintigraphy for measuring filtration dynamics 12 , 13 , while MAG3 enters the urinary tract mostly via tubular excretion and is used to detect urinary tract obstruction (in Lasix scan) 14 - 16 . In contrast, DMSA and GHA have longer tissue retention in the kidney and in other organs, and are therefore selected for obtaining static images in SPECT 9 , 10 , 17 .…”

Section: Introductionmentioning

confidence: 99%

Targeted design of a recombinant tracer for SPECT renal imaging

et al. 2021

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Rationale: A robust radiopharmaceutical has high uptake in the target and low retention in non-target tissues. However, traditional tracers for renal imaging that chemically chelate 99m Tc are excreted through the renal route with transient resident time in the kidney. Following a rational design approach, we constructed a protein-based radiotracer, designated PBT-Fc, to sequentially bind tubular neonatal Fc-receptor and subsequently proximal tubular basement membrane for its targeted sequestration in kidney parenchyma. In this process, the tracer participates in physiologic glomerular filtration and tubular reabsorption while escaping lysosomal catabolism and urinary clearance. Methods: To specifically target renal receptors in navigating the urinary passage in the kidney, we produced a recombinant fusion protein with two separate functional parts: a polybasic PBT segment derived from human Vascular Endothelial Growth Factor and Fc segment of IgG1. The chimeric fusion of PBT-Fc was labeled with radionuclide 99m Tc and tested in rodent models of kidney diseases. Planar scintigraphy and single-photon emission computerized tomography (SPECT) were performed to evaluate renal-specificity of the tracer. Results: When injected in mouse and rat, following a brief 10 - 15 min dynamic redistribution phase in circulation, ~ 95% of the [ 99m Tc]-PBT-Fc signal was concentrated in the kidney and lasted for hours without urinary loss or surrounding tissue activities. Long-lasting tracer signals in the kidney cortex in conjunction with SPECT greatly augmented the image quality in detecting pathological lesions in a variety of disease models, including ischemic acute kidney injury, drug-induced renal toxicity, and chronic kidney disease from renin-angiotensin system (RAS) overactivation. Conclusion: Exclusive renal retention of the recombinant radiotracer greatly facilitated static-phase signal acquisition by SPECT and achieved submillimeter spatial resolution of kidney alternations in glomerular and tubular disease models.

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Assessing Glomerular Filtration in Small Animals Using [68Ga]DTPA and [68Ga]EDTA with PET Imaging

Cited by 12 publications

References 24 publications

Preclinical Evaluation of [18F]FACH in Healthy Mice and Piglets: An 18F-Labeled Ligand for Imaging of Monocarboxylate Transporters with PET

Preclinical Evaluation of [18F]FACH in Healthy Mice and Piglets: An 18F-Labeled Ligand for Imaging of Monocarboxylate Transporters with PET

The next era of renal radionuclide imaging: novel PET radiotracers

Targeted design of a recombinant tracer for SPECT renal imaging

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