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Transmembrane AMPA receptor regulatory protein γ-8 (TARP γ-8) mediates various AMPA receptor functions. Recently, [11C]TARP-2105 was developed as a PET ligand for TARP γ-8 imaging. We performed a full kinetic analysis of [11C]TARP-2105 using PET with [11C]TARP-2105 for the first time. The distribution volume ( VT), which is a macro parameter consisting of the K1– k4 rate constants in the two-tissue compartment model analysis, exhibited the following rank order: hippocampus (1.4 ± 0.3) > amygdala (1.0 ± 0.2) > frontal cortex (0.9 ± 0.2) > striatum (0.8 ± 0.2) ≫ cerebellum (0.5 ± 0.1) ≈ thalamus (0.5 ± 0.1) > pons (0.4 ± 0.1 mL/cm3). These heterogenous VT values corresponded with the order of biological distribution of TARP γ-8 in the brain. To validate the reference tissue model, the binding potential (BPND) of [11C]TARP-2105 for TARP γ-8 was estimated using general methods (SRTM, MRTM0, Logan reference model, and ratio method). These BPNDs based on reference models indicated excellent correlation (R2 > 0.9) to the indirect BPNDs based on 2TCM with moderate reproducibility (%variability ≈ 10). PET with [11C]TARP-2105 enabled noninvasive BPND estimation and visual mapping of TARP γ-8 in the living rat brain.

64Cu-RaftRGD-based TRT (toxicity evaluation: hepatorenal functions and gastrointestinal state)

Purpose:Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors that are rarely curable. αVβ3 integrin (αVβ3) is overexpressed on tumoral neovessels and frequently on ovarian cancer cells. Here, using two clinically relevant αVβ3-positive OCPM mouse models, we studied the theranostic potential of an αVβ3-specific radiopeptide, 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD), and its intra- and intertumoral distribution in relation to the tumor microenvironment.Experimental Design:αVβ3-expressing peritoneal and subcutaneous models of ovarian carcinoma (IGR-OV1 and NIH:OVCAR-3) were established in nude mice. 64Cu-RaftRGD was administered either intravenously or intraperitoneally. We performed intratumoral distribution (ITD) studies, PET/CT imaging and quantification, biodistribution assay and radiation dosimetry, and therapeutic efficacy and toxicity studies.Results:Intraperitoneal administration was an efficient route for targeting 64Cu-RaftRGD to OCPMs with excellent tumor penetration. Using the fluorescence surrogate, Cy5.5-RaftRGD, in our unique high-resolution multifluorescence analysis, we found that the ITD of 64Cu-RaftRGD was spatially distinct from, but complementary to, that of hypoxia. 64Cu-RaftRGD–based PET enabled clear visualization of multiple OCPM deposits and ascites and biodistribution analysis demonstrated an inverse correlation between tumor uptake and tumor size (1.2–17.2 mm). 64Cu-RaftRGD at a radiotherapeutic dose (148 MBq/0.357 nmol) showed antitumor activities by inhibiting tumor cell proliferation and inducing apoptosis, with negligible toxicity.Conclusions:Collectively, these results demonstrate the all-in-one potential of 64Cu-RaftRGD for imaging guided radiotherapy of OCPM by targeting both tumoral neovessels and cancerous cells. On the basis of the ITD finding, we propose that pairing αVβ3- and hypoxia-targeted radiotherapies could improve therapeutic efficacy by overcoming the heterogeneity of ITD encountered with single-agent treatments.

Table S1-Post-PET biodistribution data of i.v.- and i.p.-administered 64Cu-RaftRGD in IGR-OV1-OCPM mice; Table S2-Biodistribution data of i.p.-administered 64Cu-RaftRGD; Table S3-Inverse regression equations; and Table S4-Estimation of human absorbed doses.

Supplementary Materials and Methods for integrin expression analysis, autoradiography, ITD of Cy5.5-RaftRGD in relation to the tumor microenvironment (in s.c. tumors), PET/CT or PET/CECT imaging and quantification, Ki-67 immunostaining, TUNEL assay, and quantification, survival study, and toxicity evaluation.

The aim of this study is to investigate the changes in expression of metabotropic glutamate (Glu) receptor subtype 1 (mGluR1), a key molecule involved in neuroexcitetoxicity, during excessive Glu release in the brain by PET imaging. An animal model of excessive Glu release in the brain was produced by intraperitoneally implanting an Alzet osmotic pump containing N-acetylcysteine (NAC), an activator of the cysteine/Glu antiporter, into the abdomen of rats. Basal Glu concentration in the brain was measured by microdialysis, which showed that basal Glu concentration in NAC-treated rats (0.31 µM) was higher than that in saline-treated rats (0.17 µM) at day 7 after the implantation of the osmotic pump. Similarly, PET studies with [

We developed a human-scale single-ring OpenPET (SROP) system, which had an open space allowing us access to the subject during measurement. The SROP system consisted of 160 4-layer depth-of-interaction detectors. The open space with the axial width of 430 mm was achieved with the ring axial width of 214 mm and the ring inner diameter of 660 mm. The detectors were axially shifted to each other so that the detector ring was aligned along a plane horizontally tilted by 45° against the axial direction. The system was developed as a mobile scanner to be used not only in clinical positron emission tomography (PET) rooms but also in charged-particle therapy treatment rooms as well as animal experiment rooms. Almost uniform spatial resolution better than 3 mm throughout the entire field of view (FOV) was realized with an iterative image reconstruction method. Peak absolute sensitivity was 3.1%, and there was a region with sensitivity better than 0.8% for a length of more than 700 mm. An in-beam imaging experiment conducted at the heavy ion medical accelerator in Chiba showed that the system was operable even at the highest beam intensity available for heavy-ion therapy. In addition, we conducted entire-body monkey dynamic imaging utilizing the long region inside the gantry by positioning a monkey along the direction having the longest FOV tilted by 45° against the axial direction. We concluded the developed system has a capability to realize versatile PET applications by utilizing its wide-open space and mobility in addition to high spatial resolution with sufficiently good sensitivity. -9mm]Please consider rephrasing the sentence “We concluded the developed system” for clarity.

Hypoxia caused by ischemia induces acidosis and neuroexcitotoxicity, resulting in neuronal death in the central nervous system (CNS). Monoacylglycerol lipase (MAGL) is a modulator of 2-arachidonoylglycerol (2-AG), which is involved in retrograde inhibition of glutamate release in the endocannabinoid system. In the present study, we used positron emission tomography (PET) to monitor MAGL-positive neurons and neuroinflammation in the brains of ischemic rats. Additionally, we performed PET imaging to evaluate the neuroprotective effects of an MAGL inhibitor in an ischemic injury model. Methods: Ischemic-injury rat models were induced by intraluminal right middle cerebral artery occlusion (MCAO). PET studies of the brains of the ischemic rats were performed at several experimental time points (pre-occlusion, days 2, 4, and 7 after the MCAO surgery) using [11C]SAR127303 for MAGL and [18F]FEBMP for 18 kDa translocator protein (TSPO, a hall-mark of neuroinflammation). Medication using minocycline (a well-known neuroprotective agent) or KML29 (a potent MAGL inhibitor) was given immediately after the MCAO surgery and then daily over the subsequent three days. Results: PET imaging of the ischemic rats using [11C]SAR127303 showed an acute 4decline of radioactive accumulation in the ipsilateral side at two days after MCAO surgery (ratio of the area under the curve between the ipsilateral and contralateral sides: 0.49 ± 0.04 in the cortex and 0.73 ± 0.02 in the striatum). PET imaging with [18F]FEBMP, however, showed a moderate increase in accumulation of radioactivity in the ipsilateral hemisphere on day 2 (1.36 ± 0.11), and further increases on day 4 (1.72 ± 0.15) and day 7 (1.99 ± 0.06). Treatment with minocycline or KML29 eased the decline in radioactive accumulation of [11C]SAR127303 for MAGL (minocycline-treated group: 0.82 ± 0.06 in the cortex and 0.81 ± 0.05 in the striatum; KML29-treated group: 0.72 ± 0.07 in the cortex and 0.88 ± 0.04 in the striatum) and increased uptake of [18F]FEBMP for TSPO (minocycline-treated group: 1.52 ± 0.21 in the cortex and 1.56 ± 0.11 in the striatum; KML29-treated group: 1.63 ± 0.09 in the cortex and 1.50 ± 0.17 in the striatum). In MCAO rats, minocycline treatment showed a neuroprotective effect in the sensorimotor cortex suffering from severe hypoxic injury, whereas KML29 treatment saved neurons in the striatum, including bundles of myelinated axons. Conclusions: PET imaging allowed visualization of the different neuroprotective effects of minocycline and KML29, and indicated that combination pharmacotherapy using these drugs may be an effective therapy in acute ischemia.

Diacylglycerol kinase gamma (DGKγ) is a subtype of DGK enzyme, which catalyzes ATP-dependent conversion of diacylglycerol to phosphatidic acid. DGKγ, localized in the brain, plays an important role in the central nervous system. However, its function has not been widely investigated. Positron emission tomography (PET) imaging of DGKγ validates target engagement of therapeutic DGKγ inhibitors and investigates DGKγ levels under normal and disease conditions. In this study, we designed and synthesized a series of 3-acetyl indole derivatives as candidates for PET imaging agents for DGKγ. Among the synthesized compounds, 2-((3-acetyl-1-(6-methoxypyridin-3-yl)-2-methyl-1H-indol-5-yl)oxy)-N-methylacetamide (9) exhibited potent inhibitory activity (IC50 = 30 nM) against DGKγ and desirable physicochemical properties allowing efficient blood-brain barrier penetration and low levels of undesirable nonspecific binding. The radiolabeling of 9 followed by PET imaging of wild-type and DGKγ-deficient mice and rats indicated that [11C]9 ([11C]T-278) specifically binds to DGKγ and yields a high signal-to-noise ratio for DGKγ in rodent brains.

Diacylglycerol kinase gamma (DGKγ) is a subtype of DGK enzyme which catalyzes ATPdependent conversion of diacylglycerol to phosphatidic acid. DGKγ, localized in brain, plays some important role in central nervous system. However, its function has not been widely investigated. Positron emission tomography (PET) imaging of DGKγ validates target engagement of therapeutic DGKγ inhibitors and investigates DGKγ levels under normal and disease conditions. In this study, we designed and synthesized a series of 3-acetyl indole derivatives as candidates for PET imaging agents for DGKγ. Among the synthesized compounds, 2-((3-acetyl-1-(6-methoxypyridin-3-yl)-2-methyl-1H-indol-5-yl)oxy)-N-methylacetamide (9) exhibited potent inhibitory activity (IC50 = 30 nM) against DGKγ and desirable physicochemical properties allowing efficient blood-brain barrier penetration and low levels of undesirable nonspecific binding. The radio-labeling of 9 followed by PET imaging of wild-type and DGKγ- deficient mice and rats indicated that [11C]9 ([11C]T-278) specifically binds to DGKγ and yields a high signal-noise ratio for DGKγ in rodent brains.

Background In pancreatic cancer surgery, accurate identification and resection of intrapancreatic residual tumors are quite difficult. We have developed a novel open-typed PET system (called 'OpenPET'), which enables high-resolution PET-guided surgery in real time, and demonstrated that OpenPET-guided surgery with intraperitoneally administered 64Cu-labeled anti-epidermal growth factor receptor antibody cetuximab is useful to detect and resect primary pancreatic cancer. Here, we investigated applicability of OpenPET-guided surgery for unexpected residual intrapancreatic tumors and examined its survival benefit over conventional surgery. Methods A mouse model with large (>1 cm) resectable pancreatic cancer of xPA-1-DC cells expressing red fluorescent protein was used. OpenPET-guided surgery was conducted 24 h after intraperitoneal administration of 64Cu-labeled cetuximab (7.4 MBq/mouse). For comparison, similar surgical procedures were conducted, and conventional tumor resection was attempted using only the naked eye (control). Survival rate after OpenPET-guided surgery was compared to that after control operations. Results Intraoperative OpenPET guidance enabled detection and resection of small residual tumors. Ten residual tumor specimens (3-10 mm in diameter) were intraoperatively isolated with OpenPET guidance (n = 7 mice). All isolated specimens showed tumor RFP signals. No resection of tumor tissue was performed in control group because the tumor could not be clearly detected with the naked eye alone. Mice after OpenPET-guided surgery showed significantly longer survival rates than those in control group. Conclusions OpenPET-guided surgery with 64Cu-labeled-cetuximab enabled intraoperative identification and resection of intrapancreatic small residual tumors. This technology could be useful to prevent tumor residuals during surgery and improve pancreatic cancer survival.

In pancreatic cancer surgery, accurate identification and resection of intrapancreatic residual tumors are quite difficult. We have developed a novel open-typed PET system (called 'OpenPET'), which enables high-resolution PET-guided surgery in real time, and demonstrated that OpenPET-guided surgery with intraperitoneally administered 64Cu-labeled anti-epidermal growth factor receptor antibody cetuximab is useful to detect and resect primary pancreatic cancer. Here, we investigated applicability of OpenPET-guided surgery for unexpected residual intrapancreatic tumors and examined its survival benefit over conventional surgery.

Objective. For PET imaging systems, a smaller detector ring enables less intrinsic spatial resolution loss due to the photon non-collinearity effect as well as better balance between production cost and sensitivity, and a hemispherical detector arrangement is more appropriate for brain imaging than a conventional cylindrical arrangement. Therefore, we have developed a brain-dedicated PET system with a hemispherical detector arrangement, which has been commercialized in Japan under the product name of VRAINTM. In this study, we evaluated imaging performance of VRAIN. Approach. The VRAIN used 54 detectors to form the main hemispherical unit and an additional half-ring behind the neck. Each detector was composed of a 12 × 12 array of lutetium fine silicate crystals (4.1 × 4.1 × 10 mm3) and a 12 × 12 array of silicon photomultipliers (4 × 4 mm2 active area) with the one-to-one coupling. We evaluated the physical performance of VRAIN according to the NEMA NU 2–2018 standards. Some measurements were modified so as to fit the hemispherical geometry. In addition, we performed 18F-FDG imaging in a healthy volunteer. Main results. In the phantom study, the VRAIN showed high resolution for separating 2.2 mm rods, 229 ps TOF resolution and 19% scatter fraction. With the TOF gain for a 20 cm diameter object (an assumed head diameter), the peak noise-equivalent count rate was 144 kcps at 9.8 kBq ml−1 and the sensitivity was 25 kcps MBq−1. Overall, the VRAIN provided excellent image quality in phantom and human studies. In the human FDG images, small brain nuclei and gray matter structures were clearly visualized with high contrast and low noise. Significance. We demonstrated the excellent imaging performance of VRAIN, which supported the advantages of the hemispherical detector arrangement.

Objectives: The receptor interacting protein 1 kinase (RIP1) is well-known as a key enzyme to regulate neuronal cell death, indicating relationship with several central nervous system disorders. Recently, Hou J et al has identified potent inhibitors for RIP1 [1]. Among, cyclohexyl (5-(2-acetamidobenzo[d]thiazol-6-yl)-2-methylpyridin-3-yl)carbamate (PK68) showed the highest inhibitory efficacy (mIC50 = 13 nM) for RIP1. The aim of this study is to radiolabel PK68 with 11C and to evaluate its distribution in healthy mice. Methods: [11C]PK68 was synthesized by the reaction of an amine precursor with [11C]acetyl chloride ([11C]AcCl) that was prepared by the reaction of methyl magnesium bromide with [11C]CO2, followed by chlorination with oxallyl chloride and distillation (Scheme 1), using an automated synthesis system developed in house [2]．Dynamic PET scans were conducted for 60 min (1 min × 4 frames, 2 min × 8 frames, and 5 min × 8 frames) using healthy mice. For the blocking study, the mouse was intravenously administrated with unlabeled PK68 (1 mg/kg) before staring a PET scan. Metabolite analysis of [11C]PK68 was performed using the plasma and liver samples by radio-HPLC system. Biodistribution of [11C]PK68 in mice was evaluated by measuring radioactivity in tissues of mice sacrificed at several time points (1, 5, 15, 30, and 60 min) after the injection. Results: At the end of synthesis, 670 ± 68 MBq (n = 6) of [11C]PK68 was obtained with >99% radiochemical purity and > 37 GBq/μmol of molar activity, starting from about 24 GBq of [11C]CO2. The fully-automated synthesis time was 30 min from the end of irradition. This radioactive product showed > 95% radiochemical purity within 60 min after the formulation. PET imaging with [11C]PK68 showed high uptakes in the liver and kidney of mouse in early time after the injection. Although the uptake of radioactivity in the liver was slightly decreased by treatment with unlabeled PK68, there was no significant difference between control and blocking subjects. Metabolite analysis exhibited relative high stablilty of [11C]PK68 in the plasma and liver in vivo. In ex vivo biodistribution study, it was suggested that [11C]PK68 was metabolised in the liver and removed from body via the hepatobiliary excretion and intestinal reuptake pathway. Conclusions: In this study, we successfully radiosynthesized [11C]PK68 and evaluated its dynamics and stability in vivo.

Metabotropic glutamate receptor 2 (mGlu2) is a known target for treating several central nervous system (CNS) disorders. To develop a viable positron emission tomography (PET) ligand for mGlu2, we identified new candidates 5a-i that are potent negative allosteric modulators (NAMs) of mGlu2. Among these candidates, 4-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinamide (5i, also named as [11C]MG2-1812) exhibited high potency, high subtype selectivity, and favorable lipophilicity. Compound 5i was labeled with positron-emitting carbon-11 (11C) to obtain [11C]5i in high radiochemical yield and high molar activity by O-[11C]methylation of the phenol precursor 12 with [11C]CH3I. In vitro autoradiography with [11C]5i showed heterogeneous radioactive accumulation in the brain tissue sections, ranked in the order: cortex > striatum > hippocampus > cerebellum ≫ thalamus > pons. PET study of [11C]5i indicated in vivo specific binding of mGlu2 in the rat brain. Based on the [11C]5i scaffold, further optimization for new candidates is underway to identify a more suitable ligand for imaging mGlu2.

Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors that are rarely curable. αvβ3 integrin (αvβ3) is overexpressed on tumoral neovessels and frequently on ovarian cancer cells. Here, using two clinically relevant αvβ3-positive OCPM mouse models, we studied the theranostic potential of an αvβ3-specific radiopeptide, 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD), and its intra- and intertumoral distribution in relation to the tumor microenvironment.

Metabotropic glutamate receptor 2 (mGlu2) is a known target for treating several central nervous system (CNS) disorders. To develop a viable positron emission tomography (PET) ligand for mGlu2, we identified new candidates 5a–i that are potent negative allosteric modulators (NAMs) of mGlu2. Among these candidates, 4-(2-fluoro-4-methoxyphenyl)-5-((1-methyl-1H-pyrazol-3-yl)methoxy)picolinamide (5i, also named as [11C]MG2-1812) exhibited high potency, high subtype selectivity, and favorable lipophilicity. Compound 5i was labeled with positron-emitting carbon-11 (11C) to obtain [11C]5i in high radiochemical yield and high molar activity by O-[11C]methylation of the phenol precursor 12 with [11C]CH3I. In vitro autoradiography with [11C]5i showed heterogeneous radioactive accumulation in the brain tissue sections, ranked in the order: cortex > striatum > hippocampus > cerebellum ≫ thalamus > pons. PET study of [11C]5i indicated in vivo specific binding of mGlu2 in the rat brain. Based on the [11C]5i scaffold, further optimization for new candidates is underway to identify a more suitable ligand for imaging mGlu2.

Fatty acid amide hydrolase (FAAH) is a key enzyme in the endocannabinoid system. N-(3,4-Dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide ([11C]DFMC) was developed as an irreversible-type positron emission tomography (PET) tracer for FAAH. Here, we attempted to noninvasively estimate rate constant k3 (rate of transfer to the specifically-bound compartment) as a direct index for FAAH in the rat brain. First, the two-tissue compartment model analysis including three parameters [K1−k3, two-tissue compartment model for the irreversible-type radiotracer (2TCMi)] in PET study with [11C]DFMC was conducted, which provided 0.21 ± 0.04 ml·cm−3·min−1 of the net uptake value (Ki), an indirect index for FAAH, in the FAAH-richest region (the cingulate cortex). Subsequently, to noninvasively estimate Ki value, the reference model analysis (Patlak graphical analysis reference model) was tried using a time-activity curve of the spinal cord. In that result, the noninvasive Ki value (KREF) was concisely estimated with high correlation (r > 0.95) to Ki values based on 2TCMi. Using estimated KREF value, we tried to obtain calculated-k3 based on previously defined equations. The calculated k3 was successfully estimated with high correlation (r = 0.95) to direct k3 in 2TCMi. Finally, the dose relationship study using calculated k3 demonstrated that in vivo ED50 value of [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate, a major inhibitor of FAAH, was 66.4 µg/kg in rat brain. In conclusion, we proposed the calculated k3 as an alternative index corresponding to regional FAAH concentrations and suggested that PET with [11C]DFMC enables occupancy study for new pharmaceuticals targeting FAAH. SIGNIFICANCE STATEMENT In the present study, we proposed calculated k3 as an alternative index corresponding with fatty acid amide hydrolase concentration. By using calculated k3, in vivo ED50 of [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate was successfully estimated to be 66.4 µg/kg for rats. Thus, we demonstrated the pharmacological utility of positron emission tomography with N-(3,4-dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide.

Fatty acid amide hydrolase (FAAH) is a key enzyme in the endocannabinoid system. N-(3,4-Dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide ([11C]DFMC) was developed as an irreversible-type positron emission tomography (PET) ligand for FAAH. Here, we attempted to noninvasively estimate rate constant k3 as a direct index for FAAH in the rat brain. First, the two-tissue compartment model analysis including three parameters (K1–k3, 2TCMi) in PET study with [11C]DFMC was conducted, which provided 0.21 ± 0.04 mL·cm−3·min−1 of the net uptake value (Ki), an indirect index for FAAH, in the FAAH-richest region (the cingulate cortex). Subsequently, to noninvasively estimate Ki value, the reference model analysis (Patlak Reference, PGAREF) was tried using a time-activity curve of the spinal cord. In that result, the noninvasive Ki value (KREF) was concisely estimated with high correlation (r > 0.95) to Ki values based on 2TCMi. Using estimated KREF value, we tried to obtain calculated-k3 based on previously defined equations. The caluculated-k3 was successfully estimated with high correlation (r = 0.95) to direct k3 in 2TCMi. Finally, the dose relationship study using calculated-k3 demonstrated that in vivo ED50 value of URB597, a major inhibitor of FAAH, was 66.4 µg/kg in rat brain. In conclusion, we proposed the calculated-k3 as an alternative index corresponding to regional FAAH concentrations and suggested that PET with [11C]DFMC enables occupancy study for new pharmaceuticals targeting FAAH.

Pancreatic cancer (PC) has a poor prognosis owing to difficulties in the diagnosis of resectable PC at early stages. Several clinical studies have indicated that the detection and surgery of small resectable PC (64Cu-labeled anti-epidermal growth factor receptor antibody cetuximab was intraperitoneally administered into mice. It clearly identified PC tumors ≥3 mm. In contrast, neither OpenPET with intravenous-administered 64Cu-cetuximab nor intraperitoneal/intravenous-administered 18F-FDG (a traditional PET probe) could detect PC in this model. Immuno-OpenPET-guided surgery accurately resected small PC in mice and achieved significantly prolonged survival. This technology could provide a novel diagnostic and therapeutic strategy for small resectable PC to improve patient survival.

Iodide homeostasis and thyroid hormone metabolism in the brain are potentially related to changes in the activity of the sodium iodide symporter (NIS). No radiotracers are currently available for imaging brain NIS activity. Here, we synthesized 6-[124I]iodo-9-pentylpurine that can noninvasively measure iodide efflux from the brain and showed that the efflux rate of [124I]I- in NIS knockout mice was 84% lower than that of wild-type mice. Thus, 6-[124I]iodo-9-pentylpurine would be useful for imaging brain NIS activity.

Iodide homeostasis and thyroid hormone metabolism in the brain are potentially related to changes in the activity of the sodium iodide symporter (NIS). No radiotracers are currently available for imaging brain NIS activity. Here, we synthesized 6[124I]iodo-9-pentylpurine that can noninvasively measure iodide efflux from the brain and showed that the efflux rate of [124I]I− in NIS knockout mice was 84% lower than that of wild-type mice. Thus, 6-[124I]iodo-9-pentylpurine would be useful for imaging brain NIS activity.

Background: Receptor-interacting protein 1 kinase (RIPK1) is a key enzyme in the regulation of cellular necroptosis. Recently, cyclohexyl (5-(2-acetamidobenzo[d]thiazol-6-yl)-2-methylpyridin-3-yl)carbamate (PK68, 5) has been developed as a potent inhibitor of RIPK1. Herein, we radiosynthesized [11C]PK68 as a new positron emission tomography (PET) ligand for imaging RIPK1 and evaluated its potential in vivo.Results: We synthesized [11C]PK68 by reacting amine precursor 14 with [11C]acetyl chloride. At the end of synthesis, we obtained [11C]PK68 of 1200–1790 MBq (n = 10) with >99% radiochemical purity and a molar activity of 37–99 GBq/μmol starting from 18–33 GBq of [11C]CO2. The fully automated synthesis took 30 min from the end of irradiation. In a small-animal PET study, [11C]PK68 was rapidly distributed in the liver and kidneys of healthy mice after injection, and was subsequently cleared from their bodies via hepatobiliary excretion and the intestinal reuptake pathway. Although there was no obvious specific binding of RIPK1 in the PET study, [11C]PK68 demonstrated relatively high stability in vivo, and may be used as a lead compound for further candidate development.Conclusions: In the present study, we successfully radiosynthesized [11C]PK68 and evaluated its potential in vivo. We are planning to optimize the chemical structure of [11C]PK68 and conduct further PET studies on it using pathological models.

Diacylglycerol kinase gamma (DGKγ) is a subtype of DGK enzyme which catalyzes ATP-dependent conversion of diacylglycerol to phosphatidic acid. DGKγ, localized in brain, plays some important role in central nervous system. However, its function has not been widely investigated. Positron emission tomography (PET) imaging of DGKγ validates target engagement of therapeutic DGKγ inhibitors and investigates DGKγ levels under normal and disease conditions. In this study, we designed and synthesized a series of 3-acetyl indole derivatives as candidates for PET imaging agents for DGKγ. Among the synthesized compounds, 2- ((3-acetyl-1-(6-methoxypyridin-3-yl)-2-methyl-1H-indol-5-yl)oxy)-N-methylacetamide (9) exhibited potent inhibitory activity (IC50 = 30 nM) against DGKγ and desirable physicochemical properties allowing efficient blood-brain barrier penetration and low levels of undesirable non-specific binding. The radio-labeling of 9 followed by PET imaging of wild-type and DGKγ-deficient mice and rats indicated that [11C]9 ([11C]T-278) specifically binds to DGKγ and yields a high signal-noise ratio for DGKγ in rodent brains., AIMECS 2021

チオシアネート(SCN-)は神経障害を惹起する中毒性を持つと考えられているため、脳にはSCN-を排出することでSCN-の脳内濃度を低く保つ機構の存在が示唆されているが、SCN-の排出を非侵襲的に定量評価できる方法は未だ開発されていない。SCN-排出系の定量評価が可能となれば、SCN-の中毒性の評価や排出メカニズムの解明に大きく貢献すると考えられる。本研究では、脳内排出システムの定量測定法”metabolite extrusion method”に基づき6-[11C]thiocyanatopurine誘導体([11C]TP)を設計した。[11C]TPは静脈内投与後、血液脳関門を通過して脳内に移行し、グルタチオンとの反応により[11C]SCN-を遊離することが確認された。正常マウスでは、遊離された[11C]SCN-は速やかに脳から排出されたのに対して、SCN-輸送阻害剤を前投与したマウスでは[11C]SCN-排出速度の有意な低下が認められた。以上、[11C]TPによる脳内のSCN−排出系の定量評価の可能性が示唆された。, 第61回日本核医学会学術総会

【目的】：複合癌免疫療法の開発により、免疫応答の活性化レベルを生きた生体内で評価できる診断法は強く求められている。我々は、IDO1に着目し特異的なPETプローブ11C-L-1MTrpを用い、免疫化学療法における抗腫瘍免疫応答評価のPET診断法を開発した。【方法】 抗PD1抗体、抗CTLA4抗体、CPAを組み合わせたメラノーマ免疫化学治療マウスを対象に、11C-L-1MTrpを用い、治療早期及び治療後において生体内の免疫応答状態と抗腫瘍効果を追跡した。【結果】免疫化学療法により免疫応答が賦活され、がんに対する攻撃を引き起こした状態では、腸管リンパ組織に高い放射能集積が認められた（9.44 ± 0.53%ID/g）。それに対し、治療早期の免疫低下（5.22 ± 0.32%ID/g）および治療後の免疫疲弊状態（5.40 ± 0.02%ID/g）では、腸管リンパ組織に放射能集積が低く、腸管リンパ組織における放射能集積は腫瘍相対成長率との高い相関を示した(Pearson’s r = －0.827, p ＜ 0.001)。【結論】11C-L-1MTrp PETは、生きたままで抗腫瘍免疫応答の活性化レベルを定量評価ができ、複合癌免疫療法による治療効果をリアルタイムに判別可能の診断法として期待される。, 第61回日本核医学会学術総会

我々が開発を進めているWGI(Whole Gamma Imaging)は、散乱検出器リングを吸収検出器リングへ挿入することでPETとコンプトンイメージングを融合した構造となっており、様々なガンマ線の利用を目指している。また、これまでに開発したWGI試作機は、コンプトンイメージング装置としては世界初のフルリング型ジオメトリを実現したものであった。ここで、コンプトン画像再構成の条件に着目すると、理論的にはフルリング型である必要性はなく、検出器を削減できれば設計の柔軟性向上や、コスト削減が期待できる。しかしながら、実際には散乱角度の検出限界やブロック型検出器の配置方法などの影響で、再構成条件は保証されていない。そこで、本研究では、WGI試作機の89Zr円柱ファントム測定データに対し、後処理によって検出器を制限し、909keVのコンプトン画像のアーチファクトを評価することで3次元画像再構成に必要なジオメトリ条件の検討を行った。その結果、散乱検出器、吸収検出器共に、測定対象上のすべての領域を180°以上囲うことが必要であると示唆された。, 第61回日本核医学会学術総会

Positron emission tomography (PET) is a powerful molecular imaging technique that can provide functional information of living objects. However, the spatial resolution of PET imaging has been limited to around 1 mm which makes it difficult to visualize mouse brain functions in detail. Here we report an ultrahigh resolution small animal PET scanner we developed that can provide a resolution approaching 0.6 mm to visualize the mouse brain functions with unprecedented detail.

Once a high-resolution PET detector with both depth-of-interaction and time-of-flight capabilities is established, it will be applied to various-type PET systems using a software-based coincidence method. Toward this goal, we have developed a crosshair light-sharing (CLS) detector. In this work, as the first development of a practical system based on the CLS detector, we realized a high-resolution portable small animal PET with a long axial field-of-view (FOV) of 20 cm. The system was composed of 128 CLS detectors. All devices were mounted on a pushcart, and the system was operated on a 100V power supply. The axial FOV was 207 mm, which covered the total-body of a rat. A 22Na ultra-micro hot phantom was used for spatial resolution measurement, and the NEMA NU4 image quality phantom was used for image quality test. The developed CLS-PET system successfully resolved 0.75 mm rods. Subsequently, normal mouse and rat imaging with 18F-NaF and 18F-FDG were demonstrated. For the NaF-PET, mouse and rat total-body images were obtained, and detailed bone structures were clearly imaged. For the mouse FDG-PET, cardiac FDG uptakes were clearly visualized by the CLS-PET system. In conclusion, the CLS-PET system achieved, 2021 IEEE NSS/MIC

We developed a whole gamma imaging (WGI) prototype composed of a scatterer ring insert and an absorber ring. It was the world’s first realization of a full-ring Compton camera geometry. In this study, we focused on the data sufficiency condition (DSC) for Compton image reconstruction. Contrary to PET which requires a full-ring geometry to satisfy the DSC, Compton imaging does not require a full ring theoretically. Reducing the detector-ring coverages can improve flexibility of the geometry design and reduce manufacturing costs although sensitivity is decreased. However, the DSC for reconstruction is not guaranteed in a practical situation due to actual absorber ring arrangement and detection limits in scattering angle. In this study, we experimentally assessed the DSC for the angular coverages. We evaluated image artifacts on reconstructed Compton images because, in general, images distort and exhibit artifacts when the DSC is not satisfied, degrading quantitative accuracy. We measured a cylindrical phantom filled with 89Zr solution of 10.2 MBq by the WGI prototype for 60 min and extracted 909-keV Compton events. We selected events related to the detector blocks marked as available to change detector angular coverages defined for the phantom bottom point. First, we changed the number of detectors in the scatterer ring, keeping the full-ring absorber. Next, we changed the absorber ring angular coverage by changing the number of detectors, keeping the scatterer ring at the number where the angular coverage just exceeded 180°. As a result, when the angular coverage of the scatterer detector was less than 180°, reconstructed images exhibited artifacts. The absorber ring detector with less than 180° coverage showed artifacts when used with the scatterer detector with more than 180° coverage. We concluded that angular coverages of more than 180° for both the scatterer and absorber detectors against any region on a subject are the DSC for Compton image reconstruction., IEEE NSS MIC 2021

昨年の発表では，我々が開発を進めているWGI(Whole Gamma Imaging) の小動物実証機におけるコンプトンイメージングによって，高精細なマウス画像が得られたことを報告した．高精細な画像が得られた要因の一つとして，WGI がフルリング型であることが考えられるが，実際にどの程度寄与しているのか明らかにはなっていない．そこで，本研究では，画像再構成に利用する測定データを限定し，フルリングの場合と比較することで，物体を囲むリングの範囲の変化が再構成画像へ与える影響を検討した．円筒型ファントムの測定データを用い，再構成画像を視覚的に評価した結果，散乱検出器に囲まれる範囲が180°未満の領域が物体にある場合，画像にアーチファクトが生じたが，物体全域が180°以上囲まれている場合には，フルリングと同様にアーチファクトのない画像が得られた．よって，WGI コンプトン画像再構成の完全性条件として，対象視野全域を180°以上囲む必要があることが示唆された．, 第40回日本医用画像工学会大会

Diacylglycerol kinase gamma (DGKγ) is a subtype of DGK enzyme, which catalyzes ATP-dependent conversion of diacylglycerol to phosphatidic acid. DGKγ, localized in the brain, plays an important role in the central nervous system. However, its function has not been widely investigated. Positron emission tomography (PET) imaging of DGKγ validates target engagement of therapeutic DGKγ inhibitors and investigates DGKγ levels under normal and disease conditions. In this study, we designed and synthesized a series of 3-acetyl indole derivatives as candidates for PET imaging agents for DGKγ. Among the synthesized compounds, 2-((3-acetyl-1-(6-methoxypyridin-3-yl)-2-methyl-1H-indol-5-yl)oxy)-N-methylacetamide (

Hypoxia caused by ischemia induces acidosis and neuroexcitotoxicity, resulting in neuronal death in the central nervous system (CNS). Monoacylglycerol lipase (MAGL) is a modulator of 2-arachidonoylglycerol (2-AG), which is involved in retrograde inhibition of glutamate release in the endocannabinoid system. In the present study, we used positron emission tomography (PET) to monitor MAGL-positive neurons and neuroinflammation in the brains of ischemic rats. Additionally, we performed PET imaging to evaluate the neuroprotective effects of an MAGL inhibitor in an ischemic injury model. Methods: Ischemic-injury rat models were induced by intraluminal right middle cerebral artery occlusion (MCAO). PET studies of the brains of the ischemic rats were performed at several experimental time points (pre-occlusion, days 2, 4, and 7 after the MCAO surgery) using [11C]SAR127303 for MAGL and [18F]FEBMP for 18 kDa translocator protein (TSPO, a hall-mark of neuroinflammation). Medication using minocycline (a well-known neuroprotective agent) or KML29 (a potent MAGL inhibitor) was given immediately after the MCAO surgery and then daily over the subsequent three days. Results: PET imaging of the ischemic rats using [11C]SAR127303 showed an acute decline of radioactive accumulation in the ipsilateral side at two days after MCAO surgery (ratio of the area under the curve between the ipsilateral and contralateral sides: 0.49 ± 0.04 in the cortex and 0.73 ± 0.02 in the striatum). PET imaging with [18F]FEBMP, however, showed a moderate increase in accumulation of radioactivity in the ipsilateral hemisphere on day 2 (1.36 ± 0.11), and further increases on day 4 (1.72 ± 0.15) and day 7 (1.99 ± 0.06). Treatment with minocycline or KML29 eased the decline in radioactive accumulation of [11C]SAR127303 for MAGL (minocycline-treated group: 0.82 ± 0.06 in the cortex and 0.81 ± 0.05 in the striatum; KML29-treated group: 0.72 ± 0.07 in the cortex and 0.88 ± 0.04 in the striatum) and increased uptake of [18F]FEBMP for TSPO (minocycline-treated group: 1.52 ± 0.21 in the cortex and 1.56 ± 0.11 in the striatum; KML29-treated group: 1.63 ± 0.09 in the cortex and 1.50 ± 0.17 in the striatum). In MCAO rats, minocycline treatment showed a neuroprotective effect in the sensorimotor cortex suffering from severe hypoxic injury, whereas KML29 treatment saved neurons in the striatum, including bundles of myelinated axons. Conclusions: PET imaging allowed visualization of the different neuroprotective effects of minocycline and KML29, and indicated that combination pharmacotherapy using these drugs may be an effective therapy in acute ischemia.

We have successfully developed 64Cu-cyclam-RAFT-c(-RGDfK-)4 (64Cu-RaftRGD) as a multimeric RGD-based radiopeptide for specifically targeting the transmembrane cell adhesion receptor, alphaVbeta3 integrin (aVb3). Ovarian cancer peritoneal metastases (OCPMs) are a pathophysiologically heterogeneous group of tumors. Despite advances in surgical cytoreduction and drug development, the 5-year survival rate for OCPM patients remains as low as, SNMMI2021 Annual Meeting

BackgroundIndoleamine-2,3-dioxygenase 1 (IDO1) has been intensively pursued as a therapeutic target to reverse the immunosuppressive cancer-immune milieu and promote tumor elimination. However, recent failures of phase III clinical trials with IDO1 inhibitors involved in cancer immunotherapies highlight the urgent need to develop appropriate methods for tracking IDO1 when the cancer-immune milieu is therapeutically modified.MethodsWe utilized a small-molecule radiotracer, 11C-l-1MTrp, to quantitatively and longitudinally visualize whole-body IDO1 dynamics. Specifically, we first assessed 11C-l-1MTrp in mice-bearing contralateral human tumors with distinct IDO1 expression patterns. Then, we applied 11C-l-1MTrp to longitudinally monitor whole-body IDO1 variations in immunocompetent melanoma-bearing mice treated with 1-methyl-l-tryptophan plus either chemotherapeutic drugs or antibodies targeting programmedcell death 1 and cytotoxic T-lymphocyte-associated protein 4.Results11C-l-1MTrp positron emission tomography (PET) imaging accurately delineated IDO1 expression in xenograft mouse models. Moreover, we were able to visualize dynamic IDO1 regulation in the mesenteric lymph nodes (MLNs), an off-tumor IDO1 target, where the percentage uptake of 11C-l-1MTrp accurately annotated the therapeutic efficacy of multiple combination immunotherapies in preclinical models. Remarkably, 11C-l-1MTrp signal intensity in the MLNs was inversely related to the specific growth rates of treated tumors, suggesting that IDO1 expression in the MLNs can serve as a new biomarker of the cancer-immune set point.ConclusionsPET imaging of IDO1 with 11C-l-1MTrp is a robust method to assess the therapeutic efficacy of multiple combinatorial immunotherapies, improving our understanding of the merit and challenges of IDO1 regimens. Further validation of this animal data in humans is ongoing. We envision that our results will provide a potential precision medicine paradigm for noninvasive visualizing each patient’s individual response in combinatorial cancer immunotherapy, and tailoring optimal personalized combination strategies.

Objective. The biological washout of positron emitters should be modeled and corrected in order to achieve quantitative dose range verification in charged particle therapy based on positron emission tomography (PET). This biological washout effect is affected by physiological environmental conditions such as blood perfusion and metabolism, but the correlation to tumour pathology has not been studied yet. Approach. The aim of this study was to investigate the dependence of the biological washout rate on tumour vascular status in rat irradiation. Two types of tumour vascularity conditions, perfused and hypoxic, were modelled with nude rats. The rats were irradiated by a radioactive 15O ion beam and time activity curves were acquired by dynamic in-beam PET measurement. Tumour tissue sections were obtained to observe the histology as well. The biological washout rate was derived using a single-compartment model with two decay components (medium decay, k 2m and slow decay, k 2s ). Main results. All k 2m values in the vascular perfused tumour tissue were higher than the values of the normal tissue. All k 2m values in the hypoxic tumour tissue were much lower than the values of the vascular perfused tumour tissue and slightly lower than the values of the normal tissue. Significance. The dependency of the biological washout on the tumour vasculature conditions was experimentally shown.

Phosphodiesterase 10A (PDE10A) is a newly identified therapeutic target for central-nervous-system disorders. 2-(2-(3-(4-([18F]Fluoroethoxy)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]MNI-659, [18F]5) is a useful positron-emission-tomography (PET) ligand for imaging of PDE10A in the human brain. However, the radiolabeled metabolite of [18F]5 can accumulate in the brain. In this study, using [18F]5 as a lead compound, we designed four new 18F-labeled ligands ([18F]6–9) to find one more suitable than [18F]5. Of these, 2-(2-(3-(4-([18F]fluoromethoxy-d2)phenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([18F]9) exhibited high in vitro binding affinity (Ki = 2.9 nM) to PDE10A and suitable lipophilicity (log D = 2.2). In PET studies, the binding potential (BPND) of [18F]9 (5.8) to PDE10A in the striatum of rat brains was significantly higher than that of [18F]5 (4.6). Furthermore, metabolite analysis showed much lower levels of contamin...