Repurposing radiotracers for myelin imaging: a study comparing 18F-florbetaben, 18F-florbetapir, 18F-flutemetamol,11C-MeDAS, and 11C-PiB
- 77 Downloads
Drugs promoting myelin repair represent a promising therapeutic approach in multiple sclerosis and several candidate molecules are currently being evaluated, fostering the need of a quantitative method to specifically measure myelin content in vivo. PET using the benzothiazole derivative 11C-PiB has been successfully used to quantify myelin content changes in humans. Stilbene derivatives, such as 11C-MeDAS, have also been shown to bind to myelin in animals and are considered a promising radiopharmaceutical class for myelin imaging. Fluorinated compounds from both classes are now commercially available and thus should constitute clinically useful myelin radiotracers. The aim of this study is to provide a head-to-head comparison of 18F-florbetaben, 18F-florbetapir, 18F-flutemetamol, 11C-MeDAS, and 11C-PiB with regard to brain kinetics and binding in white matter (WM).
Four baboons underwent a 90-min dynamic PET scan for each radioligand. Arterial blood samples were collected during the exam for each radiotracer, except for 18F-florbetapir, to obtain a radiometabolite-corrected input function. Standardized uptake value ratio between 75 at 90 min (SUVR75–90), binding potential (BP) estimated with Logan method with input function, and distribution volume ratio (DVR) estimated with Logan reference method (using cerebellar gray matter as reference region) were calculated in WM and compared between tracers using mixed effect models.
In WM, 18F-florbetapir had the highest SUVR75–90 (1.38 ± 0.03), followed by 18F-flutemetamol (1.34 ± 0.02), 18F-florbetaben (1.32 ± 0.07), 11C-MeDAS (1.27 ± 0.04), and 11C-PiB (1.25 ± 0.07). With regard to BP, 18F-florbetaben had the highest value (0.32 ± 0.06) compared with 18F-flutemetamol (0.20 ± 0.03), 11C-MeDAS (0.17 ± 0.03), and 11C-PiB (0.16 ± 0.03). No difference in DVR was detected between 18F-florbetaben (1.26 ± 0.06) and 18F-florbetapir (1.27 ± 0.03), but both were significantly higher in DVR than 18F-flutemetamol (1.17 ± 0.02), 11C-MeDAS (1.16 ± 0.03), and 11C-PiB (1.14 ± 0.02).
Given their higher binding and longer half-life, our study indicates that 18F-florbetapir and 18F-florbetaben are promising tracers for myelin imaging which are readily available for clinical application in demyelinating diseases.
KeywordsMyelin PET imaging Multiple sclerosis Stilbene Benzothiazole
We thank the scientific committee of the INSIGHT study (Dubois et al., Lancet Neurol. 2018), which was promoted by INSERM, for having kindly provided 18F-florbetapir PET images of test-retest human healthy subjects to verify the reproducibility of 18F-florbetapir in white matter (data not shown). A special thanks to Professor Bruno Dubois, principal investigator of the INSIGHT study, and Christiane Metzinger, who managed the data transfer.
This work was performed on a platform of France Life Imaging network partly funded by grant ANR-11-INBS-0006. The study was also funded by a grant from Progressive MS Alliance (collaborative planning award to BS) and CEA. Additional support was received by Fondation ARSEP (to BB) and FRM (Fondation pour la Recherche Médicale, to MT).
Compliance with ethical standards
Conflict of interest
Four doses of 18F-flutemetamol were freely provided by GE Healthcare. No other potential conflicts of interest relevant to this article exist.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
- 4.Heath F, Hurley SA, Johansen-Berg H, Sampaio-Baptista C. Advances in noninvasive myelin imaging. Dev Neurobiol [Internet]. Wiley-Blackwell; 2018 [cited 2019 Mar 11];78:136–51. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29082667.
- 5.Petiet A, Adanyeguh I, Aigrot M-S, Poirion E, Nait-Oumesmar B, Santin M, et al. Ultrahigh field imaging of myelin disease models: toward specific markers of myelin integrity? J Comp Neurol [Internet]. John Wiley & Sons, Ltd; 2019 [cited 2019 Mar 11]; Available from: http://doi.wiley.com/10.1002/cne.24598.
- 6.Brugarolas P, Sánchez-Rodríguez JE, Tsai H-M, Basuli F, Cheng S-H, Zhang X, et al. Development of a PET radioligand for potassium channels to image CNS demyelination. Sci Rep [Internet]. Nature Publishing Group; 2018 [cited 2018 Jun 19];8:607. Available from: http://www.nature.com/articles/s41598-017-18747-3.
- 7.Stankoff B, Wang Y, Bottlaender M, Aigrot M-S, Dolle F, Wu C, et al. Imaging of CNS myelin by positron-emission tomography. Proc Natl Acad Sci. 2006;103:9304–9 Available from: http://www.pnas.org/cgi/doi/10.1073/pnas.0600769103.CrossRefGoogle Scholar
- 8.Wu C, Tian D, Feng Y, Polak P, Wei J, Sharp A, et al. A novel fluorescent probe that is brain permeable and selectively binds to myelin. J Histochem Cytochem [Internet]. SAGE PublicationsSage CA: Los Angeles, CA; 2006 [cited 2018 Jun 19];54:997–1004. Available from: http://journals.sagepub.com/doi/10.1369/jhc.5A6901.2006.CrossRefGoogle Scholar
- 10.Gibbs-Strauss SL, Nasr KA, Fish KM, Khullar O, Ashitate Y, Siclovan TM, et al. Nerve-highlighting fluorescent contrast agents for image-guided surgery. Mol Imaging [Internet]. NIH Public Access; 2011 [cited 2018 Jun 19];10:91–101. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21439254.CrossRefGoogle Scholar
- 11.Cotero VE, Siclovan T, Zhang R, Carter RL, Bajaj A, LaPlante NE, et al. Intraoperative fluorescence imaging of peripheral and central nerves through a myelin-selective contrast agent. Mol Imaging Biol [Internet]. Springer-Verlag; 2012 [cited 2018 Jun 19];14:708–17. Available from: http://link.springer.com/10.1007/s11307-012-0555-1.
- 12.De Paula Faria D, de Vries EFJ, Sijbesma JWA, Dierckx RAJO, Buchpiguel CA, Copray S. PET imaging of demyelination and remyelination in the cuprizone mouse model for multiple sclerosis: a comparison between [11C]CIC and [11C]MeDAS. Neuroimage [Internet]. Academic Press; 2014 [cited 2018 Jun 19];87:395–402. Available from: https://www.sciencedirect.com/science/article/pii/S105381191301080X.
- 13.Wu C, Zhu J, Baeslack J, Zaremba A, Hecker J, Kraso J, et al. Longitudinal positron emission tomography imaging for monitoring myelin repair in the spinal cord. Ann Neurol [Internet]. Wiley-Blackwell; 2013 [cited 2018 Jun 19];74:688–98. Available from: http://doi.wiley.com/10.1002/ana.23965.
- 14.Glenner GG, Page DL, Eanes ED. The relation of the properties of congo red-stained amyloid fibrils to the β-conformation. J Histochem Cytochem [Internet]. SAGE PublicationsSage UK: London, England; 1972 [cited 2018 Jun 19];20:821–6. Available from: http://journals.sagepub.com/doi/10.1177/20.10.821.CrossRefGoogle Scholar
- 15.Klunk WE, Pettegrew JW, Abraham DJ. Quantitative evaluation of congo red binding to amyloid-like proteins with a beta-pleated sheet conformation. J Histochem Cytochem [Internet]. SAGE PublicationsSage CA: Los Angeles, CA; 1989 [cited 2018 Jun 19];37:1273–81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2666510.
- 16.Ridsdale RA, Beniac DR, Tompkins TA, Moscarello MA, Harauz G. Three-dimensional structure of myelin basic protein. II. Molecular modeling and considerations of predicted structures in multiple sclerosis. J Biol Chem [Internet]. American Society for Biochemistry and Molecular Biology; 1997 [cited 2018 Jun 19];272:4269–75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9020143.
- 17.Bajaj A, LaPlante NE, Cotero VE, Fish KM, Bjerke RM, Siclovan T, et al. Identification of the protein target of myelin-binding ligands by immunohistochemistry and biochemical analyses. J Histochem Cytochem [Internet]. Histochemical Society; 2013 [cited 2018 Jun 19];61:19–30. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23092790.CrossRefGoogle Scholar
- 19.Pietroboni AM, Carandini T, Colombi A, Mercurio M, Ghezzi L, Giulietti G, et al. Amyloid PET as a marker of normal-appearing white matter early damage in multiple sclerosis: correlation with CSF β-amyloid levels and brain volumes. Eur J Nucl Med Mol Imaging [Internet]. European Journal of Nuclear Medicine and Molecular Imaging; 2019;46:280–7. Available from: http://link.springer.com/10.1007/s00259-018-4182-1.CrossRefGoogle Scholar
- 24.Nelissen N, Van Laere K, Thurfjell L, Owenius R, Vandenbulcke M, Koole M, et al. Phase 1 study of the Pittsburgh compound B derivative 18F-flutemetamol in healthy volunteers and patients with probable Alzheimer disease. J Nucl Med Off Publ Soc Nucl Med. 2009;50:1251–9.Google Scholar
- 27.Auvity S, Caillé F, Marie S, Wimberley C, Bauer M, Langer O, et al. P-glycoprotein (ABCB1) inhibits the influx and increases the efflux of 11C-metoclopramide across the blood-brain barrier: a PET study on nonhuman primates. J Nucl Med Off Publ Soc Nucl Med. 2018;59:1609–15.Google Scholar
- 28.Tonietto M, Rizzo G, Veronese M, Fujita M, Zoghbi SS, Zanotti-Fregonara P, et al. Plasma radiometabolite correction in dynamic PET studies: insights on the available modeling approaches. J Cereb Blood Flow Metab [Internet]. SAGE Publications; 2016 [cited 2016 Feb 15];36:326–39. Available from: http://jcb.sagepub.com/content/36/2/326.full.
- 29.Tonietto M, Rizzo G, Veronese M, Borgan F, Bloomfield PS, Howes O, et al. A unified framework for plasma data modeling in dynamic positron emission tomography studies. IEEE Trans Biomed Eng [Internet]. IEEE; 2019;66:1447–55. Available from: https://ieeexplore.ieee.org/document/8486715/.CrossRefGoogle Scholar
- 32.Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, et al. Graphical analysis of reversible radioligand binding from time—activity measurements applied to [ N - 11 C-methyl]-(−)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab. 1990;10:740–7. Available from:. https://doi.org/10.1038/jcbfm.1990.127.CrossRefPubMedGoogle Scholar
- 33.Logan J, Fowler JS, Volkow ND, Wang G-J, Ding Y-S, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab. 1996;1:834–40 Available from: http://jcb.sagepub.com/lookup/doi/10.1097/00004647-199609000-00008.CrossRefGoogle Scholar
- 34.Bertoldo A, Rizzo G, Veronese M. Deriving physiological information from PET images: from SUV to compartmental modelling. Clin Transl Imaging [Internet]. 2014 [cited 2015 Jun 4];2:239–51. Available from: http://link.springer.com/10.1007/s40336-014-0067-x.CrossRefGoogle Scholar
- 36.Heurling K, Buckley C, Vandenberghe R, Van Laere K, Lubberink M. Separation of β-amyloid binding and white matter uptake of (18)F-flutemetamol using spectral analysis. Am J Nucl Med Mol Imaging [Internet]. 2015;5:515–26. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26550542%5Cn http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4620178.
- 37.Choi SR, Golding G, Zhuang Z, Zhang W, Lim N, Hefti F, et al. Preclinical properties of 18F-AV-45: a PET agent for a plaques in the brain. J Nucl Med. 2009;50:1887–94 Available from: http://jnm.snmjournals.org/cgi/doi/10.2967/jnumed.109.065284.CrossRefGoogle Scholar
- 39.Patt M, Schildan A, Barthel H, Becker G, Schultze-Mosgau MH, Rohde B, et al. Metabolite analysis of [18F]florbetaben (BAY 94-9172) in human subjects: a substudy within a proof of mechanism clinical trial. J Radioanal Nucl Chem. 2010;284:557–62 Available from: http://link.springer.com/10.1007/s10967-010-0514-8.CrossRefGoogle Scholar
- 40.Snellman A, Rokka J, Lopez-Picon FR, Eskola O, Wilson I, Farrar G, et al. Pharmacokinetics of [18F]flutemetamol in wild-type rodents and its binding to beta amyloid deposits in a mouse model of Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2012;39:1784–95 Available from: http://link.springer.com/10.1007/s00259-012-2178-9.CrossRefGoogle Scholar
- 41.Zeydan B, Lowe VJ, Schwarz CG, Przybelski SA, Tosakulwong N, Zuk SM, et al. Pittsburgh compound-B PET white matter imaging and cognitive function in late multiple sclerosis. Mult Scler J [Internet]. SAGE PublicationsSage UK: London, England; 2018 [cited 2018 Jun 19];24:739–49. Available from: http://journals.sagepub.com/doi/10.1177/1352458517707346.CrossRefGoogle Scholar