PET and monocarboxylate transporters

Monocarboxylate transporters (MCTs) constitute a family of 14 transmembrane proteins encoded by the SLC16A gene family. They are involved in a wide range of metabolic pathways including energy metabolism of the brain, skeletal muscle, heart, gastrointestinal tract, and tumour cells, gluconeogenesis, T-lymphocyte activation, spermatogenesis, pancreatic β-cells, thyroid hormone metabolism, and drug transport. MCT1, MCT2, MCT3, and MCT4 are responsible for proton-linked transport of acetate, pyruvate, lactate, and ketone bodies such as acetoacetate (AcAc) and β-hydroxybutyrate (β-HB) across plasma membrane down their concentration gradients. Of these, MCT4 has the lowest affinity for lactate, but due to its high turnover rate, it is important in the export of lactate by glycolytic cells, maintaining intracellular pH homeostasis. Expression of MCT4, but not MCT1, is overexpressed in hypoxic cells. Hypoxic and aerobic subpopulations of cancer cells can live in "metabolic symbiosis" by expressing MCT4 or MCT1. MCT7 exports ketone bodies from hepatocytes during fasting. MCT8 that has a high affinity for thyroid hormones T3 and T4. MCT10/TAT1 transports aromatic amino acids.

Transporter Main substrates Tissue distribution
MCT1 Lactate, pyruvate, ketone bodies, acetate, formate, niacin Ubiquitous, except α- and β-cells of pancreas. Overexpressed in cancer cells. Endothelial cells and pericytes in the brain. Red blood cells.
MCT2 Pyruvate, lactate, ketone bodies High expression in testis, moderate to low in spleen, heart, kidney, pancreas, skeletal muscle, brain (neurons and astrocytes), leucocytes
MCT3 Lactate Retinal pigment epithelium, choroid plexus
MCT4 Lactate, ketone bodies Skeletal muscle (especially glycolytic fibres), chondrocytes, leucocytes, testis, lung, brain (astrocytes), ovary, placenta, heart, liver, bone marrow
MCT5 Brain, muscle, liver, kidney, lung, ovary, placenta, heart
MCT6 Kidney, muscle, brain, heart, pancreas, prostate, lung, placenta
MCT7 Ketone bodies Liver, brain, pancreas, muscle, prostate
MCT8 T2, rT3, T3, T4 Ubiquitous
MCT9 Carnitine Endometrium, testis, ovary, breast, brain, kidney, spleen, retina
MCT10/TAT1 Aromatic amino acids, T3,T4 Kidney (basolateral), intestine, muscle, placenta, heart
MCT11 Skin, lung, ovary, breast, lung, pancreas, retinal pigment epithelium, choroid plexus
MCT12 Kidney, retina, lung, testis
MCT13 Breast, bone marrow stem cells
MCT14 Brain, heart, muscle, ovary, prostate, breast, lung, pancreas liver, spleen, thymus

Lactate and MCTs, especially MCT1 and MCT4, are important contributors to tumour aggressiveness, and MCT1/MCT4 inhibitors have been developed for treatment of cancer. Changed MCT1 and MCT4 expression is also linked to other pathophysiologies, including myocardial ischaemia, acidosis, hyperinsulinemia, liver diseases, inflammatory bowel disease, epilepsy, and neurodegenerative diseases (Gündel et al., 2021). Substrates and inhibitors of MCTs can be labelled with positron-emitting isotopes for use in PET imaging.

[18F]fluorolactate is taken up by cancer cells in vitro and tumours in vivo, and could be used to monitor MCT1-dependent lactate transport and inhibition (Van Hée et al., 2017; Braga et al., 2020).

[18F]FACH is an analogue of MCT inhibitor α-CCA, and it has high affinity and selectivity to MCT4 and MCT1. It can not pass BBB, but could be used to assess MCTs in peripheral tissues (Sadeghzadeh et al., 2020; Gündel et al., 2021).

Niacin (nicotinic acid, vitamin B3) is transported into the cells by the sodium-dependent monocarboxylate transporters (SMCT1 and SMCT2) and monocarboxylate transporter MCT1. [11C]Niacin is distributed in tissues according to expression of SMCTs and MCT1 (Bongartone et al., 2020).

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Updated at: 2023-01-26
Created at: 2023-01-12
Written by: Vesa Oikonen