Dataset Information

[¹⁸F]FEPPA PET imaging for monitoring CD68-positive microglia/macrophage neuroinflammation in nonhuman primates.

ABSTRACT:

Purpose

The aim of this study was to examine whether the translocator protein 18-kDa (TSPO) PET ligand [¹⁸F]FEPPA has the sensitivity for detecting changes in CD68-positive microglial/macrophage activation in hemiparkinsonian rhesus macaques treated with allogeneic grafts of induced pluripotent stem cell-derived midbrain dopaminergic neurons (iPSC-mDA).

Methods

In vivo positron emission tomography (PET) imaging with [¹⁸F]FEPPA was used in conjunction with postmortem CD68 immunostaining to evaluate neuroinflammation in the brains of hemiparkinsonian rhesus macaques (n = 6) that received allogeneic iPSC-mDA grafts in the putamen ipsilateral to MPTP administration.

Results

Based on assessment of radiotracer uptake and confirmed by visual inspection of the imaging data, nonhuman primates with allogeneic grafts showed increased [¹⁸F]FEPPA binding at the graft sites relative to the contralateral putamen. From PET asymmetry analysis of the images, the mean asymmetry index of the monkeys was AI = - 0.085 ± 0.018. Evaluation and scoring of CD68 immunoreactivity by an investigator blind to the treatment identified significantly more neuroinflammation in the grafted areas of the putamen compared to the contralateral putamen (p = 0.0004). [¹⁸F]FEPPA PET AI showed a positive correlation with CD68 immunoreactivity AI ratings in the monkeys (Spearman's ? = 0.94; p = 0.005).

Conclusion

These findings reveal that [¹⁸F]FEPPA PET is an effective marker for detecting increased CD68-positive microglial/macrophage activation and demonstrates sufficient sensitivity to detect changes in neuroinflammation in vivo following allogeneic cell engraftment.

SUBMITTER: Zammit M

PROVIDER: S-EPMC7410886 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Publications

[<sup>18</sup>F]FEPPA PET imaging for monitoring CD68-positive microglia/macrophage neuroinflammation in nonhuman primates.

Zammit Matthew M Tao Yunlong Y Olsen Miles E ME Metzger Jeanette J Vermilyea Scott C SC Bjornson Kathryn K Slesarev Maxim M Block Walter F WF Fuchs Kerri K Phillips Sean S Bondarenko Viktorya V Zhang Su-Chun SC Emborg Marina E ME Christian Bradley T BT

EJNMMI research 20200806 1

<h4>Purpose</h4>The aim of this study was to examine whether the translocator protein 18-kDa (TSPO) PET ligand [<sup>18</sup>F]FEPPA has the sensitivity for detecting changes in CD68-positive microglial/macrophage activation in hemiparkinsonian rhesus macaques treated with allogeneic grafts of induced pluripotent stem cell-derived midbrain dopaminergic neurons (iPSC-mDA).<h4>Methods</h4>In vivo positron emission tomography (PET) imaging with [<sup>18</sup>F]FEPPA was used in conjunction with pos ...[more]

PMID: 32761399

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Project description:PurposeThe α7 nicotinic acetylcholine receptor (nAChR) is implicated in many neuropsychiatric disorders, making it an important target for positron emission tomography (PET) imaging. The first aim of this work was to compare two α7 nAChRs PET radioligands, [18F]ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide) and [18F]DBT-10 (7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-([18F]fluorodibenzo[b,d]thiophene 5,5-dioxide), in nonhuman primates. The second aim was to assess further the quantification and test-retest variability of [18F]ASEM in humans.MethodsPET scans with high specific activity [18F]ASEM or [18F]DBT-10 were acquired in three rhesus monkeys (one male, two female), and the kinetic properties of these radiotracers were compared. Additional [18F]ASEM PET scans with blocking doses of nicotine, varenicline, and cold ASEM were acquired separately in two animals. Next, six human subjects (five male, one female) were imaged with [18F]ASEM PET for 180 min, and arterial sampling was used to measure the parent input function. Different modeling approaches were compared to identify the optimal analysis method and scan duration for quantification of [18F]ASEM distribution volume (V T). In addition, retest scans were acquired in four subjects (three male, one female), and the test-retest variability of V T was assessed.ResultsIn the rhesus monkey brain [18F]ASEM and [18F]DBT-10 exhibited highly similar kinetic profiles. Dose-dependent blockade of [18F]ASEM binding was observed, while administration of either nicotine or varenicline did not change [18F]ASEM V T. [18F]ASEM was selected for further validation because it has been used in humans. Accurate quantification of [18F]ASEM V T in humans was achieved using multilinear analysis with at least 90 min of data acquisition, resulting in V T values ranging from 19.6 ± 2.5 mL/cm3 in cerebellum to 25.9 ± 2.9 mL/cm3 in thalamus. Test-retest variability of V T was 11.7 ± 9.8%.ConclusionsThese results confirm [18F]ASEM as a suitable radiotracer for the imaging and quantification of α7 nAChRs in humans.

Project description:BackgroundExpression of translocator protein (TSPO) on the outer mitochondrial membrane of activated microglia is strongly associated with neuroinflammation. The second-generation PET ligand [18F]FEPPA specifically binds TSPO to enable in vivo visualization and quantification of neuroinflammation. We optimized a fully automated radiosynthesis method and evaluated the utility of [18F]FEPPA, the second-generation PET ligand specifically binds TSPO, in a mouse model of systemic LPS challenge to detect TSPO-associated signals of central and peripheral inflammation. In vivo dynamic PET/MR imaging was performed in LPS-induced and control mice after [18F]FEPPA administration. The relationship between the [18F]FEPPA signal and the dose of LPS was assessed. The cytokine levels (i.e., TNF-α, Il-1β, Il-6) in LPS-induced mice were measured by RT-PCR. Standard uptake value (SUV), total volume of distribution (VT) and area under the curve (AUC) were determined based on the metabolite-uncorrected plasma input function. Western blotting and immunostaining were used to measure TSPO expression in the brain.ResultsThe fully automated [18F]FEPPA radiosynthesis produced an uncorrected radiochemical yield of 30 ± 2% within 80 min, with a radiochemical purity greater than 99% and specific activity of 148.9‒216.8 GBq/µmol. Significant differences were observed in the brain after [18F]FEPPA administration: SUV, VT and AUC were 1.61 ± 0.1, 1.25 ± 0.12 and 1.58 ± 0.09-fold higher in LPS-injected mice than controls. TNF-α, Il-1β and Il-6 mRNA levels were also elevated in the brains of LPS-injected mice. Western blotting revealed TSPO (p < 0.05) and Iba-1 (p < 0.01) were upregulated in the brain after LPS administration. In LPS-injected mice, TSPO immunoactivity colocalized with Iba-1 in the cerebrum and TSPO was significantly overexpressed in the hippocampus and cerebellum. The peripheral organs (heart, lung) of LPS-injected mice had higher [18F]FEPPA signal-to-noise ratios than control mice.ConclusionsBased on the current data on ligand specificity and selectivity in central tissues using 7 T PET/MR imaging, we demonstrate that [18F]FEPPA accumulations significant increased in the specific brain regions of systemic LPS-induced neuroinflammation (5 mg/kg). Future investigations are needed to determine the sensitivity of [18F]FEPPA as a biomarker of neuroinflammation as well as the correlation between the PET signal intensity and the expression levels of TSPO.

Dataset Information

[¹⁸F]FEPPA PET imaging for monitoring CD68-positive microglia/macrophage neuroinflammation in nonhuman primates.

Purpose

Methods

Results

Conclusion

Publications

[<sup>18</sup>F]FEPPA PET imaging for monitoring CD68-positive microglia/macrophage neuroinflammation in nonhuman primates.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

[18F]FEPPA PET imaging for monitoring CD68-positive microglia/macrophage neuroinflammation in nonhuman primates.

Purpose

Methods

Results

Conclusion

Publications

[<sup>18</sup>F]FEPPA PET imaging for monitoring CD68-positive microglia/macrophage neuroinflammation in nonhuman primates.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

[¹⁸F]FEPPA PET imaging for monitoring CD68-positive microglia/macrophage neuroinflammation in nonhuman primates.