Analysis of [18F]fluoromannan PET data

Mannan

Mannan is a general term for structurally variable and complex polysaccharides which are an important part of cell walls of yeasts, fungi, and plants. Common feature of mannans is the high proportion of mannose. Mannose is a C-2 epimer of glucose; it exists in pyranose and furanose forms. Mannose has an important part in glycosylation of human (animal) proteins.

The innate immune system can identify and destroy mannan-containing cells via mannose-binding lectins, including the mannose receptor (CD206), which identifies terminal mannose in glycoproteins. CD206 is expressed on the surface of macrophages, dermal fibroblasts, keratinocytes, and mesangial cells, playing a role in both innate and adaptive immune systems.

Mannan injection causes acute inflammation, and has been used to generate a psoriasis, psoriatic arthritis, and rheumatoid arthritis mouse model (Khmaladze et al, 2014; Hagert et al., 2018). Mannan-conjugated proteins have been studied in immunotherapy and in development of vaccines against cancers and fungal infections. Common gut fungi prime the immune system and antibody production against fungal infections.

D-Mannose has been labeled with 18F and studied as a tumour and atherosclerosis imaging tracer (Furumoto et al, 2013; Tahara et al, 2014). Labelled mannose is a substrate similar to [18F]FDG, with uptake dependent on GLUTs and hexokinase, and thus the metabolic activity of the tissue. Mannose receptor has been targeted by mannose-conjugated albumin, dextran, and liposomes labelled with 68Ga and 64Cu; these tracers may be useful in detecting macrophages, and have been used to localize for example lymph nodes (Choi et al, 2011; Locke et al, 2012; Eo et al, 2015; Kang et al, 2015; Lee et al., 2017). [99mTc]tilmanocept is a mannosylated dextran with European and FDA approval for lymphatic mapping. For PET imaging, [68Ga]IRDye800-tilmanocept (Qin et al., 2019) and 18F-labelled mannosylated dextran (Al[18F]F-NOTA-D10CM) (Putri et al., 2023) have been introduced. Li et al (2016) developed 18F-labeled mannan, and found high uptake in atherosclerotic lesions in mice, as well as in macrophage-rich organs in healthy rats.

[18F]fluoromannan PET

[18F]fluoromannan PET studies have so far been only in mice and rats, reporting only the SUV (Li et al, 2016). 3 h PET scans showed that SUV reaches reasonably steady level 30-60 min after intravenous administration.

When [18F]fluoromannan is administered intraperitoneally in small mass (2 µg) in mice, the tracer is mainly cleared from circulation into the spleen, liver, thymus, and urine. When [18F]fluoromannan is co-administered with 2 or 10 mg mannan, doses which are used to induce the psoriasis, psoriatic arthritis, and rheumatoid arthritis models, the uptake into spleen and liver is reduced, and radioactivity is observed widely distributed, including the joints, bone marrow, and skin (Hagert et al., 2019).


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Literature

Ballou CE. Some aspects of the structure, immunochemistry, and genetic control of yeast mannans. Adv Enzymol Relat Areas Mol Biol. 1974; 40: 239-270. PMID: 4599414.

Choi JY, Jeong JM, Yoo BC, Kim K, Kim Y, Yang BY, Lee YS, Lee DS, Chung JK, Lee MC. Development of 68Ga-labeled mannosylated human serum albumin (MSA) as a lymph node imaging agent for positron emission tomography. Nucl Med Biol. 2011; 38(3): 371-379. doi: 10.1016/j.nucmedbio.2010.09.010.

Eo JS, Kim HK, Kim S, Lee YS, Jeong JM, Choi YH. Gallium-68 neomannosylated human serum albumin-based PET/CT lymphoscintigraphy for sentinel lymph node mapping in non-small cell lung cancer. Ann Surg Oncol. 2015; 22(2): 636-641. doi: 10.1245/s10434-014-3986-x.

Furumoto S, Shinbo R, Iwata R, Ishikawa Y, Yanai K, Yoshioka T, Fukuda H. In vitro and in vivo characterization of 2-deoxy-2-18F-fluoro-D-mannose as a tumor-imaging agent for PET. J Nucl Med. 2013; 54(8): 1354-1361. doi: 10.2967/jnumed.112.113571.

Kang CM, An GI, Choe YS. Hybrid lymph node imaging using 64Cu-labeled mannose-conjugated human serum albumin with and without indocyanine green. Nucl Med Commun. 2015; 36(10): 1026-1034. doi: 10.1097/MNM.0000000000000353.

Khmaladze I, Kelkka T, Guerard S, Wing K, Pizzolla A, Saxena A, Lundqvist K, Holmdahl M, Nandakumar KS, Holmdahl R. Mannan induces ROS-regulated, IL-17A-dependent psoriasis arthritis-like disease in mice. Proc Natl Acad Sci USA 2014; 111: E3669-E3678. doi: 10.1073/pnas.1405798111.

Li X-G, Hagert C, Siitonen R, Virtanen H, Sareila O, Liljenbäck H, Tuisku J, Knuuti J, Bergman J, Holmdahl R, Roivainen A. 18-labeling of mannan for inflammation research with positron emission tomography. ACS Med Chem Lett. 2016; 7(9): 826-830. doi: 10.1021/acsmedchemlett.6b00160.

Locke LW, Mayo MW, Yoo AD, Williams MB, Berr SS. PET imaging of tumor associated macrophages using mannose coated 64Cu liposomes. Biomaterials 2012; 33(31): 7785-7793. doi: 10.1016/j.biomaterials.2012.07.022.

Tahara N, Mukherjee J, de Haas HJ, Petrov AD, Tawakol A, Haider N, Tahara A, Constantinescu CC, Zhou J, Boersma HH, Imaizumi T, Nakano M, Finn A, Fayad Z, Virmani R, Fuster V, Bosca L, Narula J. 2-deoxy-2-[18F]fluoro-D-mannose positron emission tomography imaging in atherosclerosis. Nat Med. 2014; 20(2): 215-219. doi: 10.1038/nm.3437.



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Updated at: 2023-05-10
Created at: 2016-05-23
Written by: Vesa Oikonen