In vivo evaluation of microtubule PET ligand [11C]MPC-6827 in mice consuming chronic alcohol

1377 Objectives: According to the 2018 National Survey on Drug Use and Health (NSDUH), 14.4 million adults ages 18 and older had Alcohol Use Disorder (AUD).1 Chronic excessive alcohol consumption is a global, economic burden and estimated 88,000 people die from alcohol-related causes annually, making alcohol the third leading preventable cause of death in the United States.1 Among the alcohol-induced abnormalities, a significant decrease in the density of microtubules (MT) is reported in the postmortem samples of alcoholic brain and rodent models of chronic alcohol.2 In this presentation, we report the in vivo imaging of [11C]MPC-6827, the brain penetrant MT PET tracer in chronic alcohol treated mice and controls. Methods: Synthesis of [11C]MPC-6827 was achieved by reacting desmethyl-MPC-6827 in a GE-FXC-PRO module as reported previously.3 Imaging studies using [11C]MPC-6827 (3.7+0.8 MBq) were performed in adult male mice; either water drinking controls (n = 3) or mice that consumed 20% alcohol (w/v) for 4 months using the intermittent 2 bottle choice procedure (n = 3) that has been shown to lead to signs of alcohol dependence4.Image analyses were performed with vendor-provided software on reconstructed data. Mean activity in ROIs in whole brain, prefrontal cortex, liver and heart were measured and plotted against time (0-60 minutes) to generate time-activity curves (TACs). Results: Synthesis of [11C]MPC-6827 was achieved in 40+5% yield in >99% radiochemical purity with a molar activity of 74+18.5 GBq/μmol. Alcohol mice show a trend for lower binding of [11C]MPC-6827 in whole brain and prefrontal cortex than control mice. However, no significant differences in tracer binding were found in periphery organs such as liver and heart of alcohol treated mice compared to control mice. Conclusions: Our preliminary studies show that in chronic alcohol consuming mice, binding of the MT PET ligand [11C]MPC-6827 is reduced in brain compared to liver and heart. Therefore, [11C]MPC-6827 could be used as a PET tracer for preclinical and human brain imaging of AUD and related neurodegenerative diseases. Research support: Diane Goldberg Foundation (NYSPI/CUMC); NCATS UL1TR001873 (Reilly) Irving Institute/CTSA Translational Therapeutics, Accelerator; CTSA WFSM TIP (UL1TR001420), References: 1.https://www.niaaa.nih.gov/publications/brochures-and-fact-sheets/alcohol-facts-and-statistics 2.Labiso WL. et al. The Loss of α- and β-Tubulin Proteins Are a Pathological Hallmark of Chronic Alcohol Consumption and Natural Brain Ageing, Brain Sci. 2018, 8, 175; doi:10.3390/brainsci8090175; Wrdozain AM et al., Alcohol-Related Brain Damage in Humans, PLOS ONE, 2014, 9, e93586; Putzke et al., Long-term alcohol self-administration and alcohol withdrawal differentially modulate microtubule-associated protein 2 (MAP2) gene expression in the rat brain, Molecular Brain Research, 1998, 62(2), 196-205 . 3.Kumar JSD et al. Radiosynthesis and In vivo evaluation of [11C]MPC-6827, the first brain penetrant microtubule PET ligand, J. Med. Chem. 2018, 61(5), 2118 4.Hwa et al. Persistent escalation of alcohol drinking in C57Bl/6J mice with intermittent access to 20% ethanol, Alcohol Clin and Experimental Res. 2011, 35(11), 1938.