Language：English   Publisher：Nagoya Journal of Medical Science  

Neuroendocrine tumors (NETs) are a heterogenous group of neoplasms originating from neuroendocrine cells, most frequently found in the gastrointestinal tract and pancreas. A defining feature of NETs is the overexpression of somatostatin receptors (SSTRs), particularly subtype 2 (SSTR2), which is the primary target for both diagnostic imaging and therapeutic interventions. Peptide receptor radionuclide therapy (PRRT) using¹⁷⁷Lu-DOTATATE, a radiolabeled somatostatin analog, has emerged as a transformative alternative for patients with advanced or progressive well-differentiated NETs. Considering that SSTR expression is also present in various other tumors—including pheochromocytomas, paragangliomas, meningiomas, and medullary thyroid carcinomas—there is increasing interest in expanding the use of PRRT to other SSTR-positive malignancies. This review aimed to present evidence, explore ongoing clinical research, and highlight emerging directions for¹⁷⁷Lu-DOTATATE therapy beyond gastroenteropancreatic NETs.

DOI： 10.18999/nagjms.87.4.607

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Language：English   Publisher：Annals of Nuclear Medicine  

Purpose: This study aimed to evaluate the prognostic predictive ability of MET PET/CT-derived imaging biomarkers in patients with localized non-small cell lung cancer (NSCLC) undergoing single-fraction carbon-ion radiotherapy (CIRT) and to clarify the additional prognostic information these biomarkers can provide beyond the standard UICC staging protocol. Methods: With institutional review board approval, 67 localized NSCLC patients eligible for CIRT between 2007 and 2012 were included. Single-fraction doses of 40–50 Gy were irradiated. MET PET imaging using the Toshiba Aquiduo or Siemens Biograph 16 commenced 20 min post 740 MBq MET injection before CIRT. Experienced radiologists analyzed the images, defining metabolic tumor volume (MTV) as areas with SUV > 1.5. Statistical analysis was performed using SPSS 29, including Cox proportional hazard models for disease-free and overall survival. Results: Seven cases with Tis of T stage were excluded because of low MET radiotracer uptake. A total of 60 patients were analyzed: 36 males and 24 females with a mean age of 73 years; 35 cases of T1, 24 cases of T2, and one T3 case. The average follow-up period was 74.3 months. The univariate Cox proportional hazard analyses showed that SUVmax, MTV, and total lesion retention (TLR) correlated with disease-free survival (DFS), while no significant difference was noted in treatment dose. For overall survival (OS), solid tumor diameter, SUVmax, MTV, TLR, and sex showed significant correlations in the univariate analysis. The multivariate analysis identified MTV as the only significant prognostic factor for both DFS and OS. Kaplan–Meier survival curves further supported these findings, with log-rank tests indicating a significant difference in survival duration related to MTV in both DFS and OS. Conclusion: MTV in pre-treatment MET PET/CT would be a valuable predictor of DFS and OS of localized NSCLC treated with single-fraction CIRT.

DOI： 10.1007/s12149-025-02067-y

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Language：English   Publisher：Annals of Nuclear Medicine  

Purpose: This first-in-human study aimed to assess the biodistribution, radiation dosimetry, and safety of the novel PET tracer [3-¹¹C]AIB, a putative System A amino acid transport probe, in healthy volunteers. Methods: Six healthy male participants underwent whole-body PET/CT scans following a rapid intravenous bolus of [3-¹¹C]AIB (injected dose: 366.9 ± 17.9 MBq). Dynamic imaging of the upper abdomen was performed for 4 min post-injection, followed by static whole-body scans up to 90 min. The volumes of interest were drawn on major organs to derive time activity curves for dosimetry calculations. Safety was assessed through vital signs and laboratory tests before and after imaging. Results: High tracer uptake was observed in the salivary glands, pancreas, kidneys, and liver, whereas uptake in the brain and skeletal muscles remained low. The principal route of excretion was via the urinary tract. The effective dose was 5.1 µSv/MBq, corresponding to 1.9 mSv for 370 MBq injection comparable to other 11C-labeled amino acid tracers. No adverse events or significant changes in clinical assessments were noted. Conclusions: This first-in-man evaluation of [3-¹¹C]AIB demonstrated its safety and acceptable radiation dosimetry profile comparable to other ¹¹C-labeled amino acid tracers. The distinct biodistribution pattern with minimal uptake in the brain and skeletal muscles creates high contrast conditions for potential tumor imaging in these regions. The rapid kinetics suggest imaging protocols could be optimized for shorter acquisition times. These characteristics position [3-¹¹C]AIB as a promising radiotracer warranting investigations in cancer types with altered System A amino acid transport and metabolism.

DOI： 10.1007/s12149-025-02059-y

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Language：English   Publisher：Physical and Engineering Sciences in Medicine  

Organ segmentation using ¹⁸F-FDG PET images alone has not been extensively explored. Segmentation based methods based on deep learning (DL) have traditionally relied on CT or MRI images, which are vulnerable to alignment issues and artifacts. This study aimed to develop a DL approach for segmenting the entire liver based solely on ¹⁸F-FDG PET images. We analyzed data from 120 patients who were assessed using ¹⁸F-FDG PET. A three-dimensional (3D) U-Net model from nnUNet and preprocessed PET images served as DL and input images, respectively, for the model. The model was trained with 5-fold cross-validation on data from 100 patients, and segmentation accuracy was evaluated on an independent test set of 20 patients. Accuracy was assessed using Intersection over Union (IoU), Dice coefficient, and liver volume. Image quality was evaluated using mean (SUVmean) and maximum (SUVmax) standardized uptake value and signal-to-noise ratio (SNR). The model achieved an average IoU of 0.89 and an average Dice coefficient of 0.94 based on test data from 20 patients, indicating high segmentation accuracy. No significant discrepancies in image quality metrics were identified compared with ground truth. Liver regions were accurately extracted from ¹⁸F-FDG PET images which allowed rapid and stable evaluation of liver uptake in individual patients without the need for CT or MRI assessments.

DOI： 10.1007/s13246-025-01595-1

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Language：English   Publisher：Annals of Nuclear Medicine  

Objective: Carbon-ion radiotherapy (CIRT) is known as a promising treatment for liver tumors. However, no method has been established for estimating post-therapeutic residual liver reserve capacity (pRLRC). We previously introduced the estimation method of pRLRC using ^{99 m}Tc-galactosyl human serum albumin (^{99 m}Tc-GSA) scintigraphy (Yamazaki method). In this study, we developed “Yamazaki-variant” method for pRLRC using dose distribution data of CIRT planning. The purpose of this study was to compare pRLRC calculated by Yamazaki method and Yamazaki-variant in CIRT patients for liver tumors, and to provide the clinical advantages in both methods in terms of estimating ability of pRLRC. Methods: Patients who received CIRT for liver tumors in our hospital and underwent ^{99 m}Tc-GSA scintigraphy before and 3 months after CIRT, and contrast-enhanced liver MRI within 1 month before CIRT were included. A total of 71 patients, 21 additional to the 50 previously reported, were evaluated. The maximal removal rate of ^{99 m}Tc-GSA (GSA-Rmax) was analyzed and the GSA-Rmax of the estimated residual liver (GSA-RL) was calculated using fusion images of MRI and SPECT by Yamazaki method. In Yamazaki-variant, multiple simulations were performed using the dose distribution of the CIRT planning and SPECT fusion images to obtain higher diagnostic accuracy of GSA-RL. Two of these estimates, Validation 1 and Validation 2 by Yamazaki-variant, were used as validation data. GSA-RL and Validation 1 and 2 were compared with GSA-Rmax 3 months after CIRT (post-GSA-Rmax) using linear regression analysis. Results: GSA-RL, Validation 1 and 2 were calculated as 0.448 ± 0.214, 0.413 ± 0.199 and 0.435 ± 0.208 mg/min, respectively. Post-GSA-Rmax was 0.428 ± 0.220 mg/min. The relationship between post-GSA-Rmax and each parameter was y = 0.02 + 0.90x (R² = 0.78) for GSA-RL, y = 0.02 + 0.94x (R² = 0.79) for Estimation 1, y = 0.02 + 0.99x (R² = 0.80) for Estimation 2, respectively (P <.0001). Both Yamazaki method and Yamazaki-variant showed comparable accurate estimation ability for post-GSA-Rmax. Conclusions: The estimation of pRLRC by Yamazaki method and Yamazaki-variant was in good agreement with post-therapeutic liver reserve capacity after CIRT, and there was no difference in the accuracy of the estimation. The usefulness of Yamazaki method, which is simpler and more clinically applicable, was confirmed. Trial registration : This study is registered in UMIN Clinical Trials Registry (UMIN-CTR) as UMIN study ID: UMIN000038328 and UMIN000049770, UMIN000038174.

DOI： 10.1007/s12149-025-02048-1

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Language：English   Publisher：Journal of Radiation Research  

The rare abscopal effect in radiotherapy is thought to result from immune-activating damage-associated molecular patterns, such as high mobility group box-1 protein (HMGB1), released from cancer cells. While external irradiation of cancer cells increases HMGB1 release, it remains unclear whether internal radiotherapy with 131I-meta-iodobenzylguanidine (131I-MIBG) induces similar effects. This study aimed to determine if HMGB1 is released from human-derived cancer and normal cells after 131I-MIBG administration. The number of cells, extracellular lactate dehydrogenase (LDH) and HMGB1 were measured in H441 and human keratinocyte cell line (HaCaT) at 1 day after 2- and 10-Gy X-ray irradiation. Accumulations of 131I-MIBG in SH-SY5Y and HaCaT were measured at 60 min after 131I-MIBG (0.37, 1.85 and 3.7 MBq/well) administration. The number of cells, extracellular LDH and HMGB1 were measured at 1 day after 131I-MIBG treatment. Results: The total number of cells decreased in both H441 and HaCaT at 1 day after 10-Gy X-ray irradiation. Extracellular LDH and HMGB1 from H441 after 10-Gy X-ray irradiation were significantly increased, while no increase was observed in HaCaT after 2- and 10-Gy X-ray irradiation. After 1.85 MBq (~4-Gy by converting of PHITS simulation) and 3.7 MBq 131I-MIBG (8-Gy) administrations, the total number of cells decreased in both SH-SY5Y and HaCaT at 1 day after 131I-MIBG administration. Extracellular LDH and HMGB1 were both significantly increased in SH-SY5Y, but only extracellular LDH was significantly increased in HaCaT. HMGB1 was released from neuroblastoma cells but not from normal cells after 131I-MIBG administration. A combination of 131I-MIBG and immunotherapy may be feasible.

DOI： 10.1093/jrr/rraf034

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Language：Japanese   Publisher：Japanese Society of Radiological Technology  

DOI： 10.6009/jjrt.25-0404

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CiNii Research

Language：English   Publisher：Annals of Nuclear Medicine  

Objective: Dead-time loss is reported to be non-negligible for some patients with a high tumor burden in Lu-177 radionuclide therapy, even if the administered activity is 7.4 GBq. Hence, we proposed a simple method to shorten the apparent dead time and reduce dead-time loss using a thin lead sheet in previous work. The collimator surface of the gamma camera was covered with a lead sheet in our proposed method. While allowing the detection of 208-keV gamma photons of Lu-177 that penetrate the sheet, photons with energies lower than 208 keV, which cause dead-time loss, were shielded. In this study, we evaluated the usefulness of tungsten functional paper (TFP) for the proposed method using Monte Carlo simulation. Methods: The count rates in imaging of Lu-177 administered to patients were simulated with the International Commission on Radiological Protection (ICRP) 110 phantom using the GATE Monte Carlo simulation toolkit. The simulated gamma cameras with a 0.5-mm lead sheet, 1.2-mm TFP, or no filter were positioned closely on the anterior and posterior sides of the phantom. The apparent dead times and dead-time losses at 24 h after administration were calculated for an energy window of 208 keV ± 10%. Moreover, the dead-time losses at 24–120 h were analytically assessed using activity excretion data of Lu-177-DOTATATE. Results: The dead-time loss without a filter was 5% even 120 h after administration in patients with a high tumor burden and slow excretion, while those with a lead sheet and TFP were 0.22 and 0.58 times less than those with no filter, respectively. The count rates with the TFP were 1.3 times higher than those with the lead sheet, and the TFP could maintain primary count rates at 91–94% of those without a filter. Conclusions: Although the apparent dead time and dead-time loss with the lead sheet were shorter and less than those with TFP, those with TFP were superior to those without a filter. The advantage of TFP over the lead sheet is that the decrease in primary count rates was less.

DOI： 10.1007/s12149-024-01987-5

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Language：Japanese   Publisher：公益社団法人 日本アイソトープ協会  

DOI： 10.50955/happyokai.5.0_90

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Language：English   Publisher：Thrombosis Research  

Background: Fibroblast activation protein-α (FAP), a type-II transmembrane serine protease, is associated with wound healing, cancer-associated fibroblasts, and chronic fibrosing diseases. However, its expression in deep vein thrombosis (DVT) remains unclear. Therefore, this study investigated FAP expression and localization in DVT. Methods: We performed pathological analyses of the aspirated thrombi of patients with DVT (n = 14), classifying thrombotic areas in terms of fresh, cellular lysis, and organizing reaction components. The organizing reaction included endothelialization and fibroblastic reaction. We immunohistochemically examined FAP-expressed areas and cells, and finally analyzed FAP expression in cultured dermal fibroblasts. Results: All the aspirated thrombi showed a heterogeneous mixture of at least two of the three thrombotic areas. Specifically, 83 % of aspirated thrombi showed fresh and organizing reaction components. Immunohistochemical expression of FAP was restricted to the organizing area. Double immunofluorescence staining showed that FAP in the thrombi was mainly expressed in vimentin-positive or α-smooth muscle actin-positive fibroblasts. Some CD163-positive macrophages expressed FAP. FAP mRNA and protein levels were higher in fibroblasts with low-proliferative activity cultured under 0.1 % fetal bovine serum (FBS) than that under 10 % FBS. Fibroblasts cultured in 10 % FBS showed a significant decrease in FAP mRNA levels following supplementation with hemin, but not with thrombin. Conclusions: The heterogeneous composition of venous thrombi suggests a multistep thrombus formation process in human DVT. Further, fibroblasts or myofibroblasts may express FAP during the organizing process. FAP expression may be higher in fibroblasts with low proliferative activity.

DOI： 10.1016/j.thromres.2024.109075

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Language：English   Publisher：Plos One  

Although the standard method to evaluate skeletal muscle protein synthesis (MPS) is muscle biopsy, the method is invasive and problematic for multisite use. We conducted a small pilot study in volunteers to investigate changes in MPS according to skeletal muscle site using a noninvasive method in which 6 healthy young men were given yogurt (containing 20 g milk protein) or water, and 1 h later, L-[¹¹C]methionine ([¹¹C]Met) was administered intravenously. Dynamic PET/CT imaging of their thighs was performed for 60 min. The influx constant K<inf>i</inf> of [¹¹C]Met in skeletal muscle protein was calculated as an index of MPS using a Patlak plot, and found to be 0.6%–28% higher after ingesting yogurt than after water in 5 of the 6 volunteer participants, but it was 34% lower in the remaining participant. Overall, this indicated no significant increase in K<inf>i</inf> after ingesting milk protein. However, when the quadriceps and hamstring muscles were analyzed separately, we found a significant difference in K<inf>i</inf>. This demonstrates the potential of visualizing MPS by calculating the K<inf>i</inf> for each voxel and reconstructing it as an image, which presents unique advantages of [¹¹C]Met PET/CT for evaluating MPS, such as site-specificity and visualization.

DOI： 10.1371/journal.pone.0305620

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Language：English   Publisher：International Journal of Molecular Sciences  

[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.

DOI： 10.3390/ijms25147747

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Language：English   Publisher：Frontiers in Pharmacology  

Background: As drug-metabolizing enzyme activities are affected by a variety of factors, such as drug-drug interactions, a method to evaluate drug-metabolizing enzyme activities in real time is needed. In this study, we developed a novel SPECT imaging probe for evaluation of hepatic CYP2D activity. Methods: Iodine-123- and 125-labeled 4-iodobenzylmequitazine (^123/125I-BMQ) was synthesized with high labeling and purity. CYP isozymes involved in the metabolism of ¹²⁵I-BMQ in mouse liver microsomes were evaluated, and the utility of ^123/125I-was assessed from biological distribution and SPECT imaging evaluation in normal and CYP2D-inhibited mice. Results: In vitro metabolite analysis using mouse liver microsomes showed that ¹²⁵I-BMQ is specifically metabolized by CYP2D. Biological distribution and SPECT imaging of ^123/125I-BMQ in normal mice showed that injection ^123/125I-BMQ accumulated early in the liver and was excreted into the gallbladder and intestines. In CYP2D-inhibited mice, accumulation in the liver was increased, but accumulation in the gallbladder and intestines, the excretory organ, was delayed. Since only metabolites of ¹²⁵I-BMQ are detected in bile, visualization and measuring of the accumulation of metabolites over time in the intestine, where bile is excreted, could predict the amount of metabolites produced in the body and evaluate CYP2D activity, which would be useful in determining the dosage of various drugs metabolized by CYP2D. Conclusion: ^123/125I-BMQ is useful as a SPECT imaging probe for comprehensive and direct assessment of hepatic CYP2D activity in a minimally invasive and simple approach.

DOI： 10.3389/fphar.2024.1397288

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Language：English   Publisher：Physica Medica  

Background: The dead-time loss reportedly degrades the accuracy of dosimetry using a gamma camera for targeted radionuclide therapy with Lu-177; therefore, the dead-time loss needs to be corrected. However, the correction is challenging. In this study, we propose a novel and simple method to shorten the apparent dead time rather than correcting it through experiments and Monte Carlo simulations. Methods: An energy window of 208 keV ± 10 % is generally used for the imaging of Lu-177. Lower-energy gamma photons and X-rays of Lu-177 do not contribute to image formation but lead to dead-time losses. In our proposed method, a thin lead sheet was used to shield gamma photons and X-rays with energies lower than 208 keV, while detecting 208 keV gamma photons that penetrated the thin sheet. We measured and simulated the energy spectra and count rate characteristics of a clinical gamma camera system using a cylindrical phantom filled with a Lu-177 solution. Lead sheets of 1.0- and 0.5-mm thicknesses were used as thin shields, and the dead-time losses in tumour imaging with consumed Lu-177 were simulated. Results: The apparent dead times with lead sheets of 1.0- and 0.5-mm thicknesses and without a lead sheet were 1.7, 1.9, and 5.8 µs for an energy window of 208 keV ± 10 %, respectively. The dead-time losses could be reduced from 10 % to 1.3 % using the 1.0-mm thick lead sheet in the simulated imaging of tumour. Conclusion: Our method is promising in clinical situations and studies on Lu-177 dosimetry for tumours.

DOI： 10.1016/j.ejmp.2024.103298

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Publisher：Journal of Pharmacy and Pharmacognosy Research  

Context: Imaging the mutation status of non-small cell lung cancer (NSCLC) using radiolabeled tyrosine kinase inhibitor (TKI) analogs has garnered interest due to their unique interactions with the target epidermal growth factor receptor (EGFR). Rociletinib is a third-generation TKI that selectively inhibits the activated EGFR L858R/T790M mutations while sparing the wild-type EGFR. Aims: To synthesize a rociletinib analog for radioiodination purposes and evaluate its affinity for EGFR L858R/T790M using molecular docking and in vitro cytotoxicity assay. Methods: The rociletinib analog, N-{3-[(4-{[4-(4-acetylpiperazin-1-yl)-2-methoxyphenyl]amino}-5-(trifluoromethyl)pyrimidine-2-yl)amino] -5-iodophenyl} acrylamide (I-RMFZ), was produced by adding iodine into the diaminophenyl group and changing the position of the trifluoromethyl group. A simulation of molecular docking was conducted using the AutoDock Vina software suite. IC50 of I-RMFZ was determined using a cell cytotoxicity assay. Results: I-RMFZ was successfully synthesized through multistep reactions. Molecular docking revealed that I-RMFZ interacts with the EGFR L858R/T790M mutation. Cytotoxicity assay demonstrated that I-RMFZ had a high selectivity towards EGFR L858R/T779M mutation. Conclusions: I-RMFZ is notable for radioiodination and is anticipated to be comparable with in vivo features of rociletinib. Thus, I-RMFZ can potentially be developed as an imaging agent for NSCLC through preclinical assay.

DOI： 10.56499/jppres23.1743_12.2.231

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Language：English   Publisher：Annals of Nuclear Medicine  

Purpose: N-benzyl-N-methyl-2-[7, 8-dihydro-7-(2-[18F] fluoroethyl) -8-oxo-2-phenyl-9H-purin-9-yl] acetamide ([18F] FEDAC) is a novel positron emission tomography (PET) tracer that targets the translocator protein (TSPO; 18 kDa) in the mitochondrial outer membrane, which is known to be upregulated in various diseases such as malignant tumors, neurodegenerative diseases, and neuroinflammation. This study presents the first attempt to use [18F]FEDAC PET/CT and evaluate its biodistribution as well as the systemic radiation exposure to the radiotracer in humans. Materials and Methods: Seventeen whole-body [18F]FEDAC PET/CT (injected dose, 209.1 ± 6.2 MBq) scans with a dynamic scan of the upper abdomen were performed in seven participants. Volumes of interest were assigned to each organ, and a time–activity curve was created to evaluate the biodistribution of the radiotracer. The effective dose was calculated using IDAC-Dose 2.1. Results: Immediately after the intravenous injection, the radiotracer accumulated significantly in the liver and was subsequently excreted into the gastrointestinal tract through the biliary tract. It also showed high levels of accumulation in the kidneys, but showed minimal migration to the urinary bladder. Thus, the liver was the principal organ that eliminated [18F] FEDAC. Accumulation in the normal brain tissue was minimal. The effective dose estimated from biodistribution in humans was 19.47 ± 1.08 µSv/MBq, and was 3.60 mSV for 185 MBq dose. Conclusion: [18F]FEDAC PET/CT provided adequate image quality at an acceptable effective dose with no adverse effects. Therefore, [18F]FEDAC may be useful in human TSPO-PET imaging.

DOI： 10.1007/s12149-023-01895-0

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Language：English   Publisher：BioImpacts  

Introduction: Imaging a non-small cell lung cancer (NSCLC) using radiolabeled tyrosine kinase inhibitors (TKIs) has attracted attention due to their unique interaction with the target epidermal growth factor receptor (EGFR). Olmutinib (OTB) is one of the third-generation EGFR TKIs, which selectively inhibit EGFR L858R/T790M mutation. In this study, we aim to estimate the interaction of the iodinated OTB (I-OTB)-receptor complex by molecular docking. Furthermore, we will synthesize the I-OTB and evaluate its activity toward EGFR L858R/T790M by in vitro cytotoxicity assay. Methods: A molecular docking simulation was carried out using an AutoDock Vina program package to estimate the interaction of the ligand-receptor complex. The I-OTB, N-{3-iodo-5-[(2- {[4-(4-methylpiperazin-1-yl)phenyl]aminothieno{3,2-d}pyrimidin-4-yl)oxy]phenyl} acrylamide, was synthesized by introducing an iodine atom in the phenyl group in the 3-aryloxyanilide structure. The half inhibitory concentration (IC50) was determined by employing a 2-(2-methoxy- 4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H tetrazolium monosodium salt (WST- 8) assay to evaluate the activity of I-OTB. Results: The docking study exhibited that I-OTB could take an interaction similar to that of the parent compound. We successfully synthesized I-OTB and confirmed its structure by instrumental analysis. The binding energy of OTB and I-OTB in complex with EGFR T790M are -8.7 and -7.9 kcal/mol, respectively. The cytotoxicity assay showed that I-OTB also has an affinity towards the EGFR L858R/T790M mutation with the IC50 10.49 ± 5.64 μM compared to the EGFR wild type with the IC50 over than 10 μM. Conclusion: The cytotoxicity effect of I-OTB was comparable to that of OTB. This result indicates that the iodine substituent in OTB did not alter the parent compound selectivity toward double mutations EGFR L858R/T790M. Therefore, I-OTB is prominent for radioiodination, and [123/124I] I-OTB may be a promising candidate for EGFR L858R/T790M mutation imaging.

DOI： 10.34172/bi.2023.27774

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CiNii Research