In vivo evaluation of a microtubule PET ligand, [11C]MPC-6827, in mice following chronic alcohol consumption

Abstract

Background: Excessive alcohol consumption is a global health burden and requires a better understanding of its neurobiology. A lower density of brain microtubules is found in alcohol-related human brain disease postmortem and in rodent models of chronic alcohol consumption. Here, we report in vivo imaging studies of microtubules in brain using our recently reported Positron Emission Tomography (PET) tracer, [¹¹C]MPC-6827, in chronic alcohol-consuming adult male C57BL/6 J mice and control mice.

Methods: In vivo PET imaging studies of [¹¹C]MPC-6827 (3.7 ± 0.8 MBq) were performed in two groups of adult male mice: (1) water-consuming control mice (n = 4) and (2) mice that consumed 20% alcohol (w/v) for 4 months using the intermittent 2-bottle choice procedure that has been shown to lead to signs of alcohol dependence. Dynamic 63 min PET images were acquired using a microPET Inveon system (Siemens, Germany). PET images were reconstructed using the 3D-OSEM algorithm and analyzed using VivoQuant version 4 (Invicro, MA). Tracer uptake in ROIs that included whole brain, prefrontal cortex (PFC), liver and heart was measured and plotted as %ID/g over time (0-63 min) to generate time-activity curves (TACs).

Results: In general, a trend for lower binding of [¹¹C]MPC-6827 in the whole brain and PFC of mice in the chronic alcohol group was found compared with control group. No group difference in radiotracer binding was found in the peripheral organs such as liver and heart.

Conclusions: This pilot study indicates a trend of loss of microtubule binding in whole brain and prefrontal cortex of chronic alcohol administered mice brain compared to control mice, but no loss in heart or liver. These results indicate the potential of [¹¹C]MPC-6827 as a PET ligand for further in vivo imaging investigations of AUD in human.

Keywords: Alcoholism; Brain; Microtubule; PET; Tubulin.

Fig. 1

Chemical structure of [¹¹C]MPC-6827

Fig. 2

Ethanol consumption (g/kg) over 24 h for C57BL/6 J mice given intermittent access to alcohol. Values are reported as the mean ± standard error of the mean (SEM) from four of mice per time point

Fig. 3

Representative microPET (sagittal) image, computed from 0 to 63 min, summed images of [¹¹C]MPC-6827 in control male white mice (n = 4, left) and alcohol-consuming mice group (n = 4, right). Image represents our observation that the alcohol treated group exhibited less binding of tracer compared to controls

Fig. 4

Time-activity curves of [¹¹C]MPC-6827 binding in control water-consuming and chronic alcohol-consuming mice. A Whole brain; B prefrontal cortex. Values are reported as the mean (solid line) ± SEM (dotted line) from four pairs of mice per group. Radioactivity in whole brain and prefrontal cortex of alcohol treated mice group suggest less binding of tracer compared to controls

Fig. 5

Standardized uptake values of [¹¹C]MPC-6827 binding in control and chronic alcohol-consuming mice. A Whole brain; B prefrontal cortex. Values are reported as a box and whisker plot where from four pairs of mice per group. Whole brain SUV values were not significantly different between water (media = 0.88, n = 4) and chronic alcohol (media = 0.75, n = 4) conditions (Mann–Whitney test, U = 3, p = 0.2). However, PFC, there was a nearly significant reduction in SUV (Mann–Whitney, U = 1, p = 0.057) between water (media = 1.07, n = 4) and chronic alcohol (media = 0.89, n = 4) groups

Fig. 6

Time-activity curves of [¹¹C]MPC-6827 in control mice and chronic alcohol consuming mice in heart (A) and liver (B). Values are reported as the mean ± SEM from four pairs of mice per group. Radiotracer did not show any significant differences of binding in the heart and liver