The effectiveness of L- and D-amino acids for detecting the early stage of infection in bacterial imaging was compared. We evaluated the accumulation of ³H-L-methionine (Met), ³H-D-Met, ³H-L-alanine (Ala), and ³H-D-Ala in E. coli EC-14 and HaCaT cells. Biological distribution was assessed in control and lung-infection-model mice with EC-14 using ³H-L- and D-Met, and ¹⁸F-FDG. A maximum accumulation of ³H-L- and D-Met, and ³H-L- and D-Ala occurred in the growth phase of EC-14 in vitro. The accumulation of ³H-L-Met and L-Ala was greater than that of ³H-D-Met and D-Ala in both EC-14 and HaCaT cells. For all radiotracers, the accumulation was greater in EC-14 than in HaCaT cells at early time points. The accumulation was identified at 5 min after injection in EC-14, whereas the accumulation gradually increased in HaCaT cells over time. There was little difference in biodistribution between ³H-L-and D-Met except in the brain. ³H-L- and D-Met were sensitive for detecting areas of infection after the spread of bacteria throughout the body, whereas ¹⁸F-FDG mainly detected primary infection areas. Therefore, ¹¹C-L- and D-Met, radioisotopes that differ only in terms of ³H labeling, could be superior to ¹⁸F-FDG for detecting bacterial infection in lung-infection-model mice.

In this study, we evaluated the use of 15-(4-¹²³I-iodophenyl)-3(R,S)-methylpentadecanoic acid (¹²³I-BMIPP) to visualize fatty acid metabolism in bacteria for bacterial infection imaging. We found that ¹²³I-BMIPP, which is used for fatty acid metabolism scintigraphy in Japan, accumulated markedly in Escherichia coli EC-14 similar to ¹⁸F-FDG, which has previously been studied for bacterial imaging. To elucidate the underlying mechanism, we evaluated changes in ¹²³I-BMIPP accumulation under low-temperature conditions and in the presence of a CD36 inhibitor. The uptake of ¹²³I-BMIPP by EC-14 was mediated via the CD36-like fatty-acid-transporting membrane protein and accumulated by fatty acid metabolism. In model mice infected with EC-14, the biological distribution and whole-body imaging were assessed using ¹²³I-BMIPP and ¹⁸F-FDG. The ¹²³I-BMIPP biodistribution study showed that, 8 h after infection, the ratio of ¹²³I-BMIPP accumulated in infected muscle to that in control muscle was 1.31 at 60 min after ¹²³I-BMIPP injection. In whole-body imaging 1.5 h after ¹²³I-BMIPP administration and 9.5 h after infection, infected muscle exhibited a 1.33-times higher contrast than non-infected muscle. Thus, ¹²³I-BMIPP shows potential for visualizing fatty acid metabolism of bacteria for imaging bacterial infections.

The World Health Organization has cautioned that antimicrobial resistance (AMR) will be responsible for an estimated 10 million deaths annually by 2050. To facilitate prompt and accurate diagnosis and treatment of infectious disease, we investigated the potential of amino acids for use as indicators of bacterial growth activity by clarifying which amino acids are taken up by bacteria during the various growth phases. In addition, we examined the amino acid transport mechanisms that are employed by bacteria based on the accumulation of labeled amino acids, Na⁺ dependence, and inhibitory effects using a specific inhibitor of system A. We found that ³H-L-Ala accurately reflects the proliferative activity of Escherichia coli K-12 and pathogenic EC-14 in vitro. This accumulation in E. coli could be attributed to the amino acid transport systems being different from those found in human tumor cells. Moreover, biological distribution assessed in infection model mice with EC-14 using ³H-L-Ala showed that the ratio of ³H-L-Ala accumulated in infected muscle to that in control muscle was 1.20. By detecting the growth activity of bacteria in the body that occurs during the early stages of infection by nuclear imaging, such detection methods may result in expeditious diagnostic treatments for infectious diseases.

[¹²³I]β-methyl-p-iodophenyl-pentadecanoic acid ([¹²³I]BMIPP), which is used for nuclear medicine imaging of myocardial fatty acid metabolism, accumulates in cancer cells. However, the mechanism of accumulation remains unknown. Therefore, this study aimed to elucidate the accumulation and accumulation mechanism of [¹²³I]BMIPP in cancer cells. We compared the accumulation of [¹²³I]BMIPP in cancer cells with that of [¹⁸F]FDG and found that [¹²³I]BMIPP was a much higher accumulation than [¹⁸F]FDG. The accumulation of [¹²³I]BMIPP was evaluated in the presence of sulfosuccinimidyl oleate (SSO), a CD36 inhibitor, and lipofermata, a fatty acid transport protein (FATP) inhibitor, under low-temperature conditions and in the presence of etomoxir, a carnitine palmitoyl transferase I (CPT1) inhibitor. The results showed that [¹²³I]BMIPP accumulation was decreased in the presence of SSO and lipofermata in H441, LS180, and DLD-1 cells, suggesting that FATPs and CD36 are involved in [¹²³I]BMIPP uptake in cancer cells. [¹²³I]BMIPP accumulation in all cancer cell lines was significantly decreased at 4 °C compared to that at 37 °C and increased in the presence of etomoxir in all cancer cell lines, suggesting that the accumulation of [¹²³I]BMIPP in cancer cells is metabolically dependent. In a biological distribution study conducted using tumor-bearing mice transplanted with LS180 cells, [¹²³I]BMIPP highly accumulated in not only LS180 cells but also normal tissues and organs (including blood and muscle). The tumor-to-intestine or large intestine ratios of [¹²³I]BMIPP were similar to those of [¹⁸F]FDG, and the tumor-to-large-intestine ratios exceeded 1.0 during 30 min after [¹²³I]BMIPP administration in the in vivo study. [¹²³I]BMIPP is taken up by cancer cells via CD36 and FATP and incorporated into mitochondria via CPT1. Therefore, [¹²³I]BMIPP may be useful for imaging cancers with activated fatty acid metabolism, such as colon cancer. However, the development of novel imaging radiotracers based on the chemical structure analog of [¹²³I]BMIPP is needed.

We evaluated the whole-body distribution of orally-administered radioiodine-125 labeled acetaminophen (¹²⁵I-AP) to estimate gastrointestinal absorption of anionic drugs. ¹²⁵I-AP was added to human embryonic kidney (HEK)293 and Flp293 cells expressing human organic anion transporting polypeptide (OATP)1B1/3, OATP2B1, organic anion transporter (OAT)1/2/3, or carnitine/organic cation transporter (OCTN)2, with and without bromosulfalein (OATP and multidrug resistance-associated protein (MRP) inhibitor) and probenecid (OAT and MRP inhibitor). The biological distribution in mice was determined by oral administration of ¹²⁵I-AP with and without bromosulfalein and by intravenous administration of ¹²⁵I-AP. The uptake of ¹²⁵I-AP was significantly higher in HEK293/OATP1B1, OATP1B3, OATP2B1, OAT1, and OAT2 cells than that in mock cells. Bromosulfalein and probenecid inhibited OATP- and OAT-mediated uptake, respectively. Moreover, ¹²⁵I-AP was easily excreted in the urine when administered intravenously. The accumulation of ¹²⁵I-AP was significantly lower in the blood and urinary bladder of mice receiving oral administration of both ¹²⁵I-AP and bromosulfalein than those receiving only ¹²⁵I-AP, but significantly higher in the small intestine due to inhibition of OATPs and/or MRPs. This study indicates that whole-body distribution after oral ¹²⁵I-AP administration can be used to estimate gastrointestinal absorption in the small intestine via OATPs, OATs, and/or MRPs by measuring radioactivity in the urinary bladder.