[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.

The cystine/glutamate antiporter xCT has attracted attention due to its role in maintaining redox homeostasis. Noninvasive techniques for visualizing xCT expression in tumors provide valuable diagnostic information for evaluating tumor biology. Therefore, we developed and evaluated a novel SPECT radiopharmaceutical to visualize xCT expression in cancer cells based on inhibitors. We designed and synthesized a radioiodinated SSZ derivative ([¹²⁵I]I-SSZd), based on the structure of sulfasalazine (SSZ)-an xCT inhibitor. We radioiodinated 4-hydroxy-L-phenylglycine (L-HPG) and 4-hydroxy-D-phenylglycine (D-HPG) to synthesize [¹²⁵I]I-L-HPG and [¹²⁵I]I-D-HPG, respectively. The affinities of [¹²⁵I]I-SSZd, [¹²⁵I]I-L-HPG, and [¹²⁵I]I-D-HPG to xCT were evaluated using SSZ and cystine inhibition assays in two human-derived colon cancer cell lines (LS180 and DLD-1). xCT expression was quantified using real-time polymerase chain reaction. In vivo, the biodistribution of [¹²⁵I]I-L-HPG was examined in tumor-bearing mice. Stability analysis was performed in mice liver and kidney homogenates. [¹²⁵I]I-L-HPG showed high affinity for xCT. [¹²⁵I]I-D-HPG exhibited some affinity for xCT. xCT was not involved in [¹²⁵I]I-SSZd accumulation. The gene expression levels of xCT were higher in LS180 than in DLD-1 cells. [¹²⁵I]I-L-HPG and [¹²⁵I]I-D-HPG showed high accumulation in LS180 cells. [¹²⁵I]I-L-HPG showed higher accumulation than [¹²⁵I]I-D-HPG in both cell lines. In the kidneys, [¹²⁵I]I-L-HPG accumulation decreased over time. In the thyroid, [¹²⁵I]I-L-HPG accumulation increased over time; however, deiodination did not occur in mice. Tumor-to-muscle ratio was >2.0 at almost all timepoints for both types of tumor-bearing mice, and the maximum tumor-to-large intestine ratio reached 4.0 in LS180 tumors with high xCT expression. In tumors, [¹²⁵I]I-L-HPG shows promise as a radiopharmaceutical by exhibiting high affinity for xCT.

The rare abscopal effect during radiotherapy is thought to be caused by the release of immune-stimulated damage-associated molecular patterns, such as high mobility group box-1 protein (HMGB1), from cancer cells. Although external irradiation of cancer cells increases HMGB1 release, it is not clear if HMGB1 is released from cells after administering 131I-labeled m-iodobenzylguanidine (131I-MIBG) as an internal targeted radiotherapeutic agent. This study aimed to determine if HMGB1 is released from human-derived cancer and normal cells after administering 131I-MIBG. Methods: Extracellular lactate dehydrogenase (LDH) and HMGB1 released from H441 (human-derived lung adenocarcinoma cell line) and HaCaT (human keratinocyte cell line) 1 day after 2- and 10-Gy X-ray irradiation were measured. Accumulations of 131I-MIBG in SH-SY5Y (human-derived neuroblastoma cell line) and HaCaT were measured 60 min after administering 131I-MIBG (0.37, 1.85, 3.7 MBq/well). Extracellular LDH and HMGB1 released from SH-SY5Y and HaCaT 1 day after administering 131I-MIBG were also measured. Results: The extracellular LDH and HMGB1 released from H441 after 10-Gy X-ray irradiation were significantly increased. However, the extracellular LDH and HMGB1 released from HaCaT after 2-Gy and 10-Gy X-ray irradiation were not increased. After administering 1.85 MBq and 3.7 MBq 131I-MIBG, the extracellular LDH and HMGB1 released from SH-SY5Y were both significantly increased, but only the extracellular LDH released from HaCaT was significantly increased. Conclusions: HMGB1 was released from neuroblastomas but not from normal cells after 131I-MIBG administration, suggesting that a combination of 131I-MIBG and immunotherapy may be feasible.

Background: The prevalence of nontuberculous mycobacteria (NTM) infection is on the rise, surpassing that of pulmonary tuberculosis in Japan. Current standard therapy for NTM infection involves long-term treatment of at least 1.5 years, with low success rates and a high relapse rate. ^99mTc-diethylenetriaminepentaacetic acid-galactosyl-human serum albumin (^99mTc-GSA) is used for human liver imaging. In this study, we utilized ^99mTc-GSA as a probe to detect Mycobacterium avium (M. avium), a major pathogen in NTM pulmonary diseases (NTM-PDs). Our aim was to investigate the non-invasive detection of M. avium using ^99mTc-GSA on Single-Photon Emission Computed Tomography (SPECT). Methods: The accumulation of ^99mTc-GSA in M. avium was investigated in vitro. In vivo, SPECT images were obtained after the administration of ^99mTc-GSA to an M. avium thigh infection model. Subsequently, the contrast difference in accumulated ^99mTc-GSA between infected and non-infected thighs was calculated using SPECT imaging. Furthermore, SPECT images were obtained for thighs infected with varying bacterial loads, and the accumulation was compared between them. Results: In vitro, we observed that ^99mTc-GSA accumulates in M. avium. In vivo, SPECT images demonstrated the specific accumulation of ^99mTc-GSA at the infection site, with this accumulation being correlated with the bacterial load. Conclusions: ^99mTc-GSA specifically accumulates in M. avium, and SPECT can be used to monitor the distribution and quantity of M. avium in animals. By utilizing these measures, ^99mTc-GSA can be targeted to the site of infection and used as a bacterial probe.

Sodium-glucose co-transporters (SGLTs), particularly SGLT1 and SGLT2, play an active role in glucose uptake by cancer cells and have gained attention as novel therapeutic targets. However, the development of nuclear medicine imaging agents specific to SGLTs has not yet been explored. This study aimed to develop and evaluate radiolabeled glycoside derivatives targeting SGLT1 and SGLT2 for cancer imaging. β-Arbutin, a structural analog of methyl-α-D-glucopyranoside (MDG) which is SGLTs substrate, and phlorizin, a SGLT2 inhibitor, were selected as glycoside compounds for radioiodination, [¹²⁵I]β-arbutin and [¹²⁵I]phlorizin were synthesized. The accumulation was measured in HEK293 cells transfected overexpress GLUT1, GLUT3, SGLT1, or SGLT2. Subsequent accumulation studies were conducted in LS180 and DLD-1 cancer cell lines, and the gene expression levels were quantified by real-time polymerase chain reaction (PCR). Biodistribution of both radiotracers was examined in tumor-bearing mice. [¹²⁵I]β-Arbutin had affinity for SGLT1 and SGLT2, whereas [¹²⁵I]phlorizin had affinity for SGLT1 and GLUT3. [¹²⁵I]β-Arbutin accumulated preferentially in SGLT1-high LS180 cells, whereas [¹²⁵I]phlorizin accumulated in GLUT3-high DLD-1 cells. In vivo, [¹²⁵I]β-arbutin exhibited favorable biodistribution with low brain and thyroid accumulation, rapid blood clearance, and high tumor-to-blood ratios in SGLT1-expressing tumors. Although [¹²⁵I]phlorizin also showed low brain and thyroid accumulation, its blood clearance was slower and tumor-to-blood ratios were lower. [¹²⁵I]β-Arbutin is a promising radiopharmaceutical candidate for imaging cancers with high SGLTs expression.