Imaging niacin trafficking with positron emission tomography reveals in vivo monocarboxylate transporter distribution

Abstract

Introduction A sufficient dietary intake of the vitamin niacin is essential for normal cellular function. Niacin is transported into the cells by the monocarboxylate transporters: sodium-dependent monocarboxylate transporter (SMCT1 and SMCT2) and monocarboxylate transporter (MCT1). Despite the importance of niacin in biological systems, surprisingly, its in vivo biodistribution and trafficking in living organisms has not been reported. The availability of niacin radiolabelled with the short-lived positron emitting radionuclide carbon-11 ([ 11 C]niacin) would enable the quantitative in vivo study of this endogenous micronutrient trafficking using in vivo PET molecular imaging. Methods [ 11 C]Niacin was synthesised via a simple one-step, one-pot reaction in a fully automated system using cyclotron-produced carbon dioxide ([ 11 C]CO 2 ) and 3-pyridineboronic acid ester via a copper-mediated reaction. [ 11 C]Niacin was administered intravenously in healthy anaesthetised mice placed in a high-resolution nanoScan PET/CT scanner. To further characterize in vivo [ 11 C]niacin distribution in vivo , mice were challenged with either niacin or AZD3965, a potent and selective MCT1 inhibitor. To examine niacin gastrointestinal absorption and body distribution in vivo , no-carrier-added (NCA) and carrier-added (CA) [ 11 C]niacin formulations were administered orally. Results Total synthesis time including HPLC purification was 25 ± 1 min from end of [ 11 C]CO 2 delivery. [ 11 C]Niacin was obtained with a decay corrected radiochemical yield of 17 ± 2%. We report a rapid radioactivity accumulation in the kidney, heart, eyes and liver of intravenously administered [ 11 C]niacin which is consistent with the known in vivo SMCTs and MCT1 transporter tissue expression. Pre-administration of non-radioactive niacin decreased kidney-, heart-, ocular- and liver-uptake and increased urinary excretion of [ 11 C]niacin. Pre-administration of AZD3965 selectively decreased [ 11 C]niacin uptake in MCT1-expressing organs such as heart and retina. Following oral administration of NCA [ 11 C]niacin, a high level of radioactivity accumulated in the intestines. CA abolished the intestinal accumulation of [ 11 C]niacin resulting in a preferential distribution to all tissues expressing niacin transporters and the ...

Radiosynthesis, Preclinical, and Clinical Positron Emission Tomography Studies of Carbon-11 Labeled Endogenous and Natural Exogenous Compounds

“…[Carboxyl- 11 C]niacin was administered intravenously in healthy mice, and dynamic PET data were acquired for 60 min (Figures 98 and 99). 420 [Carboxyl- 11 C]niacin accumulated in the kidney, liver, retina, and heart, where SMCTs and MCT1 transporters are primarily expressed. Pre-administration of nonradioactive niacin or a potent MCT1 inhibitor (AZD3965) increased urinary excretion and decreased the uptake in MCT1-expressing organs of [Carboxyl- 11 C]niacin was administered orally in mice, and emission data were acquired for 120 min (Figures 98 and 99).…”

“…[ Carboxyl - 11 C]­niacin was administered intravenously in healthy mice, and dynamic PET data were acquired for 60 min (Figures and ) . [ Carboxyl - 11 C]­niacin accumulated in the kidney, liver, retina, and heart, where SMCTs and MCT1 transporters are primarily expressed.…”

“…[ Carboxyl - 11 C]­niacin PET images of no-niacin added (A,B), niacin-challenged mice (C,D) AZD3965-challenged (E,F) mice. Reproduced with permission from ref . Copyright 2020 Elsevier.…”

“…[ Carboxyl - 11 C]­niacin PET images after oral administration in no-niacin added (A–C) and niacin-challenged (D–F) mice. Reproduced with permission from Bongarzone ref . Copyright 2020 Elsevier.…”

“…424 In 2020, Bongarzone et al synthesized [carboxyl- 11 C]niacin via a simple, rapid, one-step Cu-mediated 11 C-carboxylation reaction in a fully automated system using [ 11 C]CO 2 , 3pyridine boronic acid pinacol ester precursor (Figure 97). 420 The 10 min reaction at 110 °C used TMEDA as a base/ligand, CuI as a catalyst, and KF/K2.2.2 as a fluoride ion source in DMF. The product was obtained with a RCY of 17 ± 2%, RCP >99%, and A m of 7 ± 1 GBq/μmol at EOD.…”