Microtubules

Microtubules (MTs) are cytoskeletal polymers formed of repeating, non-covalently bound α- and β-tubulin heterodimers. Microtubules serve as intracellular conveyor belt for vesicles, granules, and organelles like mitochondria and chromosomes. In mammalian brain, MTs comprise ∼20% of total brain protein content. Problems in MT dynamics lead to imbalance in cellular functions, and are involved in brain diseases, cancer, and birth disorders. The stability of microtubules (MTs) is disrupted early in AD and other related dementias. Microtubule-targeting drugs are in various stages of clinical development, especially for cancer treatment. Vinca alkaloids, paclitaxel, and derivatives of colchicine have already been used as drugs.

Microtubule-targeting PET radiopharmaceuticals for cancer imaging include [11C]paclitaxel, [18F]fluoropaclitaxel, and [11C]docetaxel (van der Veldt & Lammertsma, 2014). Since docetaxel and paclitaxel are substrates of efflux transporters (P-gp, MDR1, BCRP), they have little uptake brain and are not suitable for brain imaging. [11C]Colchicine accumulation in multiple drug resistant cancer cells and tumours is markedly reduced (Levchenko et al., 2000). Several other radioligands are in development and testing, including [11C]WX-132-18B (Sai et al., 2020).

[11C]MPC-6827

MPC-6827 (verubulin, Azixa) is a blood brain barrier penetrating drug molecule that selectively binds microtubules with high affinity (∼1.5 nM). It suppresses tumour growth in a variety of cancer animal models, and could be used for treatment of glioblastoma and other cancers. MPC-6827 has been labelled with 11C for use as a PET radiopharmaceutical (Kumar et al., 2018; Damuka et al., 2020). In vitro autoradiography with [11C]MPC-6827 ([11C]verubulin) has shown higher uptake in AD patient tissue compared with healthy controls (Lindberg et al., 2021). [11C]MPC-6827 binds destabilized MTs more eagerly than stabilized MTs, and the uptake increases with brain Aβ/tau burden (Damuka et al., 2022). [11C]MPC-6827 has shown high stability in serum and brain samples of rats (Bansode et al., 2023).


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Literature

Brunden KR, Lee VM, Smith AB 3rd, Trojanowski JQ, Ballatore C. Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs. Neurobiol Dis. 2017; 105: 328-335. doi: 10.1016/j.nbd.2016.12.021.

Eira J, Silva CS, Sousa MM, Liz MA. The cytoskeleton as a novel therapeutic target for old neurodegenerative disorders. Prog Neurobiol. 2016; 141: 61-82. doi: 10.1016/j.pneurobio.2016.04.007.

Janke C. The tubulin code: molecular components, readout mechanisms, and functions. J Cell Biol. 2014; 206(4): 461-472. doi: 10.1083/jcb.201406055.

van der Veldt AA, Lammertsma AA. In vivo imaging as a pharmacodynamic marker. Clin Cancer Res. 2014; 20(10): 2569-2577. doi: 10.1158/1078-0432.CCR-13-2666.



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Updated at: 2023-08-17
Created at: 2023-08-17
Written by: Vesa Oikonen