Assessment of basal TSPO expression and [18F]DPA-714 biodistribution in healthy mice and post-ischemic brain using PET imaging
DOI:
https://doi.org/10.15392/2319-0612.2024.2812Keywords:
MicroPET, [18F]DPA-714, biodistribution, TSPOAbstract
Positron emission tomography (PET) is an important tool in preclinical studies in small animals, providing real-time insights into biochemical, metabolic, physiological, and functional processes. PET imaging also enables the assessment of biological responses and biodistribution of novel radiolabeled compounds within a single animal, minimizing the need for larger animal groups. In particular, PET imaging with [18F]DPA-714, a Translocator Protein (TSPO) ligand, has shown high predictive and prognostic value in diseases associated with neuroinflammation and correlates well with functional outcomes. In this study, basal expression of TSPO was investigated in vivo in C57BL/6 mice and PET was proposed as a method to track biodistribution of new molecules. Male C57BL/6 mice aged 6–9 weeks and weighing 20–30 g were divided into healthy and ischemic groups. The ischemic group was subjected to transient global cerebral ischemia induced by 25 min of bilateral common carotid artery occlusion (BCCAO) followed by reperfusion. Baseline imaging of [18F]DPA-714 biodistribution was performed in healthy mice with static whole-body scans at 0-20, 20-40, 40-60, and 60-80 min post-injection intervals. After ischemia, PET scans were used to examine the cerebral uptake of [18F]DPA-714. The results confirm that PET is an effective, non-invasive technique for biodistribution studies. Analysis of SUVmean, SUVmax, and SUVpeak metrics showed increased sensitivity for increased uptake in the brain following ischemia, highlighting its importance in preclinical neuroinflammation models. Furthermore, baseline uptake of [18F]DPA-714 was observed in multiple organs, reflecting the baseline expression of TSPO and its metabolic and clearance pathways. The comparable baseline uptake observed in the brain and muscle underscores its potential as a reliable marker for studying TSPO-related inflammatory processes.
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[1] VERMEULEN, K. et al. Design and challenges of radiopharmaceuticals. Seminars in Nuclear Medicine, v. 49, n. 5, p. 339-356, 2019. DOI: https://doi.org/10.1053/j.semnuclmed.2019.07.001
[2] RADIOISOTOPES, IAEA; SERIES, RADIOPHARMACEUTICALS. Guidance for preclinical studies with radiopharmaceuticals. International Atomic Energy Agency: Vienna, Austria, 2021.
[3] CHERRY, S. R., SORENSO, J. A., & PHELPS, M. E. (2012). Physics in Nuclear Medicine. Philadelphia, PA: Elsevier Health Sciences, 2012. ISBN: 9781416051985 DOI: https://doi.org/10.1016/B978-1-4160-5198-5.00001-0
[4] PHELPS, M. E. Positron emission tomography provides molecular imaging of biological processes. Proceedings of the National Academy of Sciences of the United States of America, v. 97, n. 16, p. 9226–9233, 2000. DOI: https://doi.org/10.1073/pnas.97.16.9226
[5] CHERRY, S. R.; GAMBHIR, S. S. Use of positron emission tomography in animal research. ILAR Journal, v. 42, n. 3, p. 219–232, 2001. DOI: https://doi.org/10.1093/ilar.42.3.219
[6] HUTCHINS, G. D. et al. Small animal PET imaging. ILAR Journal, v. 49, n. 1, p. 54–65, 2008. DOI: https://doi.org/10.1093/ilar.49.1.54
[7] ZHANG, L. et al. Recent developments on PET radiotracers for TSPO and their applications in neuroimaging. Acta Pharmaceutica Sinica. B, v. 11, n. 2, p. 373–393, 2021. DOI: https://doi.org/10.1016/j.apsb.2020.08.006
[8] PAPADOPOULOS, V. et al. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends in Pharmacological Sciences, v. 27, n. 8, p. 402–409, 2006. DOI: https://doi.org/10.1016/j.tips.2006.06.005
[9] JAMES, M. L. et al. DPA-714, a new translocator protein–specific ligand: Synthesis, radiofluorination, and pharmacologic characterization. Journal of Nuclear Medicine, v. 49, n. 5, p. 814–822, 2008. DOI: https://doi.org/10.2967/jnumed.107.046151
[10] CHEN, M.-K.; GUILARTE, T. R. Translocator protein 18 kDa (TSPO): Molecular sensor of brain injury and repair. Pharmacology & Therapeutics, v. 118, n. 1, p. 1–17, 2008. DOI: https://doi.org/10.1016/j.pharmthera.2007.12.004
[11] GUILARTE, T. R. et al. Imaging neuroinflammation with TSPO: A new perspective on the cellular sources and subcellular localization. Pharmacology & Therapeutics, v. 234, p. 108048, 2021. DOI: https://doi.org/10.1016/j.pharmthera.2021.108048
[12] SONG, Y. S. et al. TSPO expression modulatory effect of acetylcholinesterase inhibitor in the ischemic stroke rat model. Cells (Basel, Switzerland), v. 10, n. 6, p. 1350, 2021. DOI: https://doi.org/10.3390/cells10061350
[13] MARTÍN, A. et al. Evaluation of the PBR/TSPO radioligand [18F]DPA-714 in a rat model of focal cerebral ischemia. Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism, v. 30, n. 1, p. 230–241, 2010. DOI: https://doi.org/10.1038/jcbfm.2009.205
[14] CHEN, P. et al. PET imaging for the early evaluation of ocular inflammation in diabetic rats by using [(18)F]-DPA-714. Experimental Eye Research, v. 245, p. 109986, 2024. DOI: https://doi.org/10.1016/j.exer.2024.109986
[15] KUSZPIT, K. et al. [(18)F]DPA-714 PET imaging reveals global neuroinflammation in Zika virus-infected mice. Molecular Imaging and Biology, v. 20, n. 2, p. 275–283, 2018. DOI: https://doi.org/10.1007/s11307-017-1118-2
[16] CHEN, Y. et al. PET imaging of retinal inflammation in mice exposed to blue light using [18F]-DPA-714. Molecular Vision, v. 28, p. 507, 31 dez. 2022.
[17] RODRÍGUEZ-CHINCHILLA, T. et al. [18F]-DPA-714 PET as a specific in vivo marker of early microglial activation in a rat model of progressive dopaminergic degeneration. European Journal of Nuclear Medicine and Molecular Imaging, v. 47, n. 11, p. 2602–2612, out. 2020. DOI: https://doi.org/10.1007/s00259-020-04772-4
[18] ZHANG, S. et al. Radiopharmaceuticals and their applications in medicine. Signal transduction and targeted therapy, v. 10, n. 1, p. 1, 2025. DOI: https://doi.org/10.1038/s41392-024-02041-6
[19] TREUTING, P. M.; DINTZIS, S. M.; MONTINE, K. S. Comparative anatomy and histology: A mouse, rat, and human atlas. 2. ed. San Diego, CA, USA: Academic Press, 2017. ISBN 978-0-12-802900-8.
[20] SANTOS, E. V. DOS et al. Applicability of [18F]FDG/PET for investigating rosmarinic acid preconditioning efficacy in a global stroke model in mice. Brazilian Journal of Pharmaceutical Sciences, v. 59, p. e21555, 2023. DOI: https://doi.org/10.1590/s2175-97902023e21555
[21] SILVA, B. et al. The 5-lipoxygenase (5-LOX) inhibitor zileuton reduces inflammation and infarct size with improvement in neurological outcome following cerebral ischemia. Current Neurovascular Research, v. 12, n. 4, p. 398–403, 2015. DOI: https://doi.org/10.2174/1567202612666150812150606
[22] SUH, J. W. et al. CT-PET weighted image fusion for separately scanned whole body rat. Medical Physics, v. 39, n. 1, p. 533–542, 2012. DOI: https://doi.org/10.1118/1.3672167
[23] VICIDOMINI, C. et al. In vivo imaging and characterization of [18F] DPA-714, a potential new TSPO ligand, in mouse brain and peripheral tissues using small-animal PET. Nuclear Medicine and Biology, v. 42, n. 3, p. 309-316, 2015. DOI: https://doi.org/10.1016/j.nucmedbio.2014.11.009
[24] KELLER, T. et al. [(18)F]F-DPA for the detection of activated microglia in a mouse model of Alzheimer’s disease. Nuclear Medicine and Biology, v. 67, p. 1–9, 2018. DOI: https://doi.org/10.1016/j.nucmedbio.2018.09.001
[25] YANAMOTO, K. et al. In vivo imaging and quantitative analysis of TSPO in rat peripheral tissues using small-animal PET with [18F]FEDAC. Nuclear Medicine and Biology, v. 37, n. 7, p. 853–860, 2010. DOI: https://doi.org/10.1016/j.nucmedbio.2010.04.183
[26] FOOKES, C. J. R. et al. Synthesis and biological evaluation of substituted [18F]imidazo[1,2-a]pyridines and [18F]pyrazolo[1,5-a]pyrimidines for the study of the peripheral benzodiazepine receptor using positron emission tomography. Journal of Medicinal Chemistry, v. 51, n. 13, p. 3700–3712, 2008. DOI: https://doi.org/10.1021/jm7014556
[27] ARLICOT, N. et al. Initial evaluation in healthy humans of [18F]DPA-714, a potential PET biomarker for neuroinflammation. Nuclear Medicine and Biology, v. 39, n. 4, p. 570–578, 2012. DOI: https://doi.org/10.1016/j.nucmedbio.2011.10.012
[28] RUPPRECHT, R. et al. Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nature Reviews. Drug discovery, v. 9, n. 12, p. 971–988, 2010. DOI: https://doi.org/10.1038/nrd3295
[29] EBERL, S. et al. Preclinical in vivo and in vitro comparison of the translocator protein PET ligands [18F]PBR102 and [18F]PBR111. European Journal of Nuclear Medicine and Molecular Imaging, v. 44, n. 2, p. 296–307, 2016. DOI: https://doi.org/10.1007/s00259-016-3517-z
[30] KELLER, T. et al. Radiosynthesis and preclinical evaluation of [(18)F]F-DPA, A novel pyrazolo[1,5a]pyrimidine acetamide TSPO radioligand, in healthy Sprague Dawley rats. Molecular Imaging and Biology, v. 19, n. 5, p. 736–745, 2017. DOI: https://doi.org/10.1007/s11307-016-1040-z
[31] KONG, X. et al. 18F-DPA-714 PET Imaging for Detecting Neuroinflammation in Rats with Chronic Hepatic Encephalopathy. Theranostics, v. 6, n. 8, p. 1220–1231, 1 jan. 2016. DOI: https://doi.org/10.7150/thno.15362
[32] SALERNO, S. et al. TSPO radioligands for neuroinflammation: An overview. Molecules (Basel, Switzerland), v. 29, n. 17, 2024. DOI: https://doi.org/10.3390/molecules29174212
[33] PEYRONNEAU, M.-A. et al. Metabolism and quantification of [(18)F]DPA-714, a new TSPO positron emission tomography radioligand. Drug Metabolism and Disposition, v. 41, n. 1, p. 122–131, 2013. DOI: https://doi.org/10.1124/dmd.112.046342
[34] ENDRES, C. J. et al. Radiation dosimetry and biodistribution of the TSPO ligand 11C-DPA-713 in humans. Journal of Nuclear Medicine, v. 53, n. 2, p. 330–335, 2012. DOI: https://doi.org/10.2967/jnumed.111.094565
[35] SHAH, S. et al. PET imaging of TSPO expression in immune cells can assess organ-level pathophysiology in high-consequence viral infections. Proceedings of the National Academy of Sciences of the United States of America, v. 119, n. 15, 2022. DOI: https://doi.org/10.1073/pnas.2110846119
[36] UZUEGBUNAM, B. C. et al. Radiotracers for imaging of inflammatory biomarkers TSPO and COX-2 in the brain and in the periphery. International Journal of Molecular Sciences, v. 24, n. 24, 2023. DOI: https://doi.org/10.3390/ijms242417419
[37] PINTO, S. R. et al. In vivo studies: comparing the administration via and the impact on the biodistribution of radiopharmaceuticals. Nuclear Medicine and Biology, v. 41, n. 9, p. 772–774, 2014. DOI: https://doi.org/10.1016/j.nucmedbio.2014.05.141
[38] DE LUCA, G. M. R.; HABRAKEN, J. B. A. Method to determine the statistical technical variability of SUV metrics. EJNMMI Physics, v. 9, n. 1, p. 40, 2022. DOI: https://doi.org/10.1186/s40658-022-00470-2
[39] DONG, R. et al. Effects of microglial activation and polarization on brain injury after stroke. Frontiers in Neurology, v. 12, p. 620948, 2021. DOI: https://doi.org/10.3389/fneur.2021.620948
[40] YENARI, M. A.; KAUPPINEN, T. M.; SWANSON, R. A. Microglial activation in stroke: therapeutic targets. Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics, v. 7, n. 4, p. 378–391, 2010. DOI: https://doi.org/10.1016/j.nurt.2010.07.005
[41] SARIKAYA, I.; ALBATINEH, A. N.; SARIKAYAA, A. Effect of various blood glucose levels on regional FDG uptake in the brain. Asia Oceania Journal of Nuclear Medicine & Biology, v. 8, n. 1, p. 46–53, Inverno 2020.
[42] RIBEIRO, M.-J. et al. Could 18 F-DPA-714 PET imaging be interesting to use in the early post-stroke period? EJNMMI Research, v. 4, n. 1, 6 jun. 2014. DOI: https://doi.org/10.1186/s13550-014-0028-4
[43] WANG, Y. et al. PET imaging of neuroinflammation in a rat traumatic brain injury model with radiolabeled TSPO ligand DPA-714. European Journal of Nuclear Medicine and Molecular Imaging, v. 41, n. 7, p. 1440–1449, 11 mar. 2014. DOI: https://doi.org/10.1007/s00259-014-2727-5
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Copyright (c) 2024 Brígida Gomes de Almeida Schirmer, Juliana de Oliveira Silva, Douglas Boniek Silva Navarro, João Vitor Reis Marques, Mariana Duarte de Souza, Ianara Pereira Silva, Juliana Batista da Silva, Carlos Malamut

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