PET Study of MCT1 activity under physiological and pathological conditions

Abstract

Monocarboxylate transporter (MCT)1 is a potential drug target in oncological and metabolic diseases. Promising results have recently been reported from the phase I clinical trial of an MCT1-targeted cancer treatment with the drug candidate AZD3965 conducted by AstraZeneca. However, the clinical trial has opened several key questions to be answered, and one of them is how to profile the whole-body MCT1 expression dynamics and activity to facilitate treatment protocol design. Positron emission tomography (PET) is an ideal technique to quantify whole-body drug target expression in a non-invasive manner and can be done in longitudinal protocols when necessary. Our research group has recently created a novel radioprobe [18F]niacin for PET quantification of MCT1 in vivo. My thesis aims to perform a proof-of-concept study of using [18F]niacin PET to measure whole-body MCT1 activity under physiological and pathological conditions. Five cohorts of mice were included. In cohort A, healthy mice with normal immunity were used. In cohort B, mice with immunodeficiency were used. In cohort C, mice were treated under sleep fragmentation conditions before PET imaging. In cohort D, mice were placed in the chamber but without sleep fragmentation treatment to clarify chamber-induced stress factors. In cohort E, melanoma model mice were used. All the mice were PET imaged for 60 minutes in dynamic mode, and 19 organs and tissues were collected immediately after PET imaging. Tissue uptake of [18F]niacin was quantified by radioactivity measurements, and tissue uptake kinetics were analysed and compared among the mice. In dynamic PET image analysis, statistically significantly higher uptake of the radiotracer was noted in wild-type mice compared to immunocompromised and melanoma mice in the brain, lung, myocardium, liver, and muscle. In comparison with the sleep-fragmented mice and healthy wild-type mice, the only significant difference in uptake was noted in muscles. None of the analysed tissues showed significant differences in uptake between the healthy wild type and the in-chamber control models. Brain, lungs, liver, myocardium, and muscles showed statistically significant differences between the melanoma model and the healthy wild-type model. In comparison with immunocompromised mice and sleep-fragmented mice, tracer uptake in the brain, myocardium, muscle, liver, and kidney showed a statistically significant association. Between the immunocompromised mice and chamber controls, a significant difference in uptake in the brain, lung, myocardium, liver, and muscle was noted. With respect to sleep-fragmented mice and in-chamber controls, there was no statistically significant difference noted in brain, lung, myocardium, muscle, liver, kidney and bone. In the ex vivo biodistribution study where radioactivity measurements were analysed, they maintained an overall similar consistency to the dynamic PET data, but differences were noted due to the single time point data in the ex vivo measurements. In ex vivo biodistribution data, whole blood, plasma, blood cells, pancreas, spleen, ovaries brown fat and harderian glands showed statistically significant higher tracer uptakes in the sleep fragmented and healthy controls compared to immunocompromised group. MCT1 expression is a complex dynamic process. The MCT1 expression and activity differ depending on the immunity status, sleep status and disease status as in melanoma. The PET tracer [18F]niacin is a promising probe for non-invasive whole-body monitoring of MCT1 activity.