Dataset Information

PET imaging of soluble epoxide hydrolase in non-human primate brain with [¹⁸F]FNDP.

ABSTRACT:

Purpose

Soluble epoxide hydrolase (sEH) is a promising candidate positron emission tomography (PET) imaging biomarker altered in various disorders, including vascular cognitive impairment (VCI), Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and depression, known to regulate levels of epoxyeicosatrienoic acids (EETs) and play an important role in neurovascular coupling. [¹⁸F]FNDP, a PET radiotracer for imaging sEH, was evaluated through quantitative PET imaging in the baboon brain, radiometabolite analysis, and radiation dosimetry estimate.

Methods

Baboon [¹⁸F]FNDP dynamic PET studies were performed at baseline and with blocking doses of the selective sEH inhibitor AR-9281 to evaluate sEH binding specificity. Radiometabolites of [¹⁸F]FNDP in mice and baboons were measured by high-performance liquid chromatography. Regional brain distribution volume (V_T) of [¹⁸F]FNDP was computed from PET using radiometabolite-corrected arterial input functions. Full body distribution of [¹⁸F]FNDP was studied in CD-1 mice, and the human effective dose was estimated using OLINDA/EXM software.

Results

[¹⁸F]FNDP exhibited high and rapid brain uptake in baboons. AR-9281 blocked [¹⁸F]FNDP uptake dose-dependently with a baseline V_T of 10.9?±?2.4?mL/mL and a high-dose blocking V_T of 1.0?±?0.09?mL/mL, indicating substantial binding specificity (91.70?±?1.74%). The V_ND was estimated as 0.865?±?0.066?mL/mL. The estimated occupancy values of AR-9281 were 99.2?±?1.1% for 1?mg/kg, 88.6?±?1.3% for 0.1?mg/kg, and 33.8?±?3.8% for 0.02?mg/kg. Murine biodistribution of [¹⁸F]FNDP enabled an effective dose estimate for humans (0.032?mSv/MBq). [¹⁸F]FNDP forms hydrophilic radiometabolites in murine and non-human primate plasma. However, only minute amounts of the radiometabolites entered the animal brain (Conclusions[¹⁸F]FNDP is a highly sEH-specific radiotracer that is suitable for quantitative PET imaging in the baboon brain. [¹⁸F]FNDP holds promise for translation to human subjects.

SUBMITTER: Du Y

PROVIDER: S-EPMC7310027 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

PET imaging of soluble epoxide hydrolase in non-human primate brain with [<sup>18</sup>F]FNDP.

Du Yong Y Minn Il I Foss Catherine C Lesniak Wojciech G WG Hu Feng F Dannals Robert F RF Pomper Martin G MG Horti Andrew G AG

EJNMMI research 20200622 1

<h4>Purpose</h4>Soluble epoxide hydrolase (sEH) is a promising candidate positron emission tomography (PET) imaging biomarker altered in various disorders, including vascular cognitive impairment (VCI), Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and depression, known to regulate levels of epoxyeicosatrienoic acids (EETs) and play an important role in neurovascular coupling. [<sup>18</sup>F]FNDP, a PET radiotracer for imaging sEH, was evaluated through quantitative PET imaging in ...[more]

PMID: 32572592

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Project description:Soluble epoxide hydrolase (sEH) is a bifunctional enzyme located within cytosol and peroxisomes that converts epoxides to the corresponding diols and hydrolyzes phosphate monoesters. It serves to inactivate epoxyeicosatrienoic acids (EETs), which are generated in the brain to couple neuronal activity and cerebral blood flow in normal and pathologic states. Altered regulation of sEH was observed previously in various neuropathologic disorders including vascular dementia and stroke. Inhibitors of sEH are pursued as agents to mitigate neuronal damage after stroke. We developed N-(3,3-diphenylpropyl)-6-18F-fluoronicotinamide (18F-FNDP), which proved highly specific for imaging of sEH in the mouse and nonhuman primate brain with PET.Methods18F-FNDP was synthesized from the corresponding bromo precursor. sEH inhibitory activity of 18F-FNDP was measured using an sEH inhibitor screening assay kit. Biodistribution was undertaken in CD-1 mice. Binding specificity was assayed in CD-1 and sEH knock-out mice and Papio anubis (baboon) through pretreatment with an sEH inhibitor to block sEH binding. Dynamic PET imaging with arterial blood sampling was performed in 3 baboons, with regional tracer binding quantified using distribution volume. The metabolism of 18F-FNDP in baboons was assessed using high-performance liquid chromatography.Results18F-FNDP (inhibition binding affinity constant, 1.73 nM) was prepared in 1 step in a radiochemical yield of 14% ± 7%, specific radioactivity in the range of 888-3,774 GBq/μmol, and a radiochemical purity greater than 99% using an automatic radiosynthesis module. The time of preparation was about 75 min. In CD-1 mice, regional uptake followed the pattern of striatum > cortex > hippocampus > cerebellum, consistent with the known brain distribution of sEH, with 5.2% injected dose per gram of tissue at peak uptake. Blockade of 80%-90% was demonstrated in all brain regions. Minimal radiotracer uptake was present in sEH knock-out mice. PET baboon brain distribution paralleled that seen in mouse, with a marked blockade (95%) noted in all regions indicating sEH-mediated uptake of 18F-FNDP. Two hydrophilic metabolites were identified, with 20% parent compound present at 90 min after injection in baboon plasma.Conclusion18F-FNDP can be synthesized in suitable radiochemical yield and high specific radioactivity and purity. In vivo imaging experiments demonstrated that 18F-FNDP targeted sEH in murine and nonhuman primate brain specifically. 18F-FNDP is a promising PET radiotracer likely to be useful for understanding the role of sEH in a variety of conditions affecting the central nervous system.

Project description:PurposeThe aim of our study was to investigate the efficacy of 18F-Fluciclovine brain PET imaging in recurrent gliomas, and to compare the utility of these images to that of contrast enhanced magnetic resonance imaging (MRI) and to [11C-methyl]-L-methionine (11C-Methionine) PET imaging. We also sought to gain insight into the factors affecting the uptake of 18F-FACBC in both tumors and normal brain, and specifically to evaluate how the uptake in these tissues varied over an extended period of time post injection.MethodsTwenty-seven patients with recurrent or progressive primary brain tumor (based on clinical and MRI/CT data) were studied using dynamic 18F-Fluciclovine brain imaging for up to 4 h. Of these, 16 patients also had 11C-Methionine brain scans. Visual findings, semi-quantitative analyses and pharmacokinetic modeling of a subset of the 18F-Fluciclovine images was conducted. The information derived from these analyses were compared to data from 11C-Methionine and to contrast-enhanced MRI.Results18F-Fluciclovine was positive for all 27 patients, whereas contrast MRI was indeterminate for three patients. Tumor 18F-Fluciclovine SUVmax ranged from 1.5 to 10.5 (average: 4.5?±?2.3), while 11C-Methionine's tumor SUVmax ranged from 2.2 to 10.2 (average: 5.0?±?2.2). Image contrast was higher with 18F-Fluciclovine compared to 11C-Methionine (p?<?0.0001). This was due to 18F-Fluciclovine's lower background in normal brain tissue (0.5?±?0.2 compared to 1.3?±?0.4 for 11C-Methionine). 18F-Fluciclovine uptake in both normal brain and tumors was well described by a simple one-compartment (three-parameter: Vb,k1,k2) model. Normal brain was found to approach transient equilibrium with a half-time that varied greatly, ranging from 1.5 to 8.3 h (mean 2.7?±?2.3 h), and achieving a consistent final distribution volume averaging 1.4?±?0.2 ml/cc. Tumors equilibrated more rapidly (t1/2ranging from 4 to 148 min, average 57?±?51 min), with an average distribution volume of 3.2?±?1.1 ml/cc. A qualitative comparison showed that the rate of normal brain uptake of 11C-Methionine was much faster than that of 18F-Fluciclovine.ConclusionTumor uptake of 18F-Fluciclovine correlated well with the established brain tumor imaging agent 11C-Methionine but provided significantly higher image contrast. 18F-Fluciclovine may be particularly useful when the contrast MRI is non-diagnostic. Based on the data gathered, we were unable to determine whether Fluciclovine uptake was due solely to recurrent tumor or if inflammation or other processes also contributed.

Dataset Information

PET imaging of soluble epoxide hydrolase in non-human primate brain with [¹⁸F]FNDP.

Purpose

Methods

Results

Publications

PET imaging of soluble epoxide hydrolase in non-human primate brain with [<sup>18</sup>F]FNDP.

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Dataset Information

PET imaging of soluble epoxide hydrolase in non-human primate brain with [18F]FNDP.

Purpose

Methods

Results

Publications

PET imaging of soluble epoxide hydrolase in non-human primate brain with [<sup>18</sup>F]FNDP.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

PET imaging of soluble epoxide hydrolase in non-human primate brain with [¹⁸F]FNDP.