[en] We aimed to determine the effect of carbon ion irradiation on the uptake of N-benzyl-N-11C-methyl-2-(7-methyl-8-oxo-2-phenyl-7, 8-dihydro-9H-purin-9-yl)acetamide ([¹¹C]DAC), a positron emission tomography (PET) ligand for the peripheral-type benzodiazepine receptor (PBR), in tumor cells and tumor-bearing mice. Spontaneous murine fibrosarcoma (NFSa) cells were implanted into the right hind legs of syngeneic C3H male mice. Conditioning irradiation with 290 MeV/u carbon ions was delivered to the 7- to 8-mm tumors In vitro uptake of [¹¹C]DAC was measured in single NFSa cells isolated from NFSa-bearing mice after irradiation. In vivo biodistribution of [¹¹C]DAC in NFSa-bearing mice was determined by small animal PET scanning and dissection. In vitro autoradiography was performed using tumor sections prepared from mice after PET scanning. In vitro and in vivo uptake of [¹¹C]DAC in single NFSa cells and NFSa-bearing mice was significantly reduced by carbon ion irradiation. The decrease in [¹¹C]DAC uptake in the tumor sections was mainly due to the change in PBR expression. In conclusion, [¹¹C]DAC PET responded to the change in PBR expression in tumors caused by carbon ion irradiation in this study. Thus, [¹¹C]DAC is a promising predictor for evaluating the effect of carbon ion radiotherapy. (author)

[en] Gefitinib (Iressa) is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. Recent studies confirmed that gefitinib interacted with the breast cancer resistance protein (BCRP) at submicromolar concentrations, whereas other multidrug transporters, including P-glycoprotein (P-gp), showed much lower reactivity toward gefitinib. Recently, many tracers for positron emission tomography (PET) have been prepared to study P-gp function in vivo; however, PET tracers had not been evaluated for both P-gp and BCRP modulation in the brain. Therefore, we evaluated in vivo brain penetration-mediated P-gp and BCRP in mice using [¹¹C]gefitinib. Co-injection with gefitinib (over 50 mg/kg), a nonspecific P-gp modulator cyclosporin A (50 mg/kg), and the dual P-gp and BCRP modulator GF120918 (over 5 mg/kg) induced an increase in the brain uptake of [¹¹C]gefitinib in mice 30 min after injection. In the PET study of mice, the radioactivity level in the brain with co-injection of GF120918 (5 mg/kg) was three- to fourfold higher than that in control after initial uptake. The radioactivity level in the brain in P-gp and Bcrp knockout mice was approximately eightfold higher than that in wild-type mice 60 min after injection. In conclusion, [¹¹C]gefitinib is a promising PET tracer to evaluate the penetration of gefitinib into the brain by combined therapy with P-gp or BCRP modulators, and into brain tumors. Furthermore, PET study with GF120918 is a promising approach for evaluating brain penetration-mediated P-gp and BCRP.

[en] 2-(2-(3-(4-(2-[¹⁸F]Fluoroethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione ([¹⁸F]MNI-659, [¹⁸F]1) is a useful PET radiotracer for imaging phosphodiesterase 10A (PDE10A) in human brain. [¹⁸F]1 has been previously prepared by direct [¹⁸F]fluorination of a tosylate precursor 2 with [¹⁸F]F⁻. The aim of this study was to determine the conditions for the [¹⁸F]fluorination reaction to obtain [¹⁸F]1 of high quality and with sufficient radioactivity for clinical use in our institute. Moreover, we synthesized [¹⁸F]1 by [¹⁸F]fluoroethylation of a phenol precursor 3 with [¹⁸F]fluoroethyl bromide ([¹⁸F]FEtBr), and the outcomes of [¹⁸F]fluorination and [¹⁸F]fluoroethylation were compared.

[en] Highlights: • The simplified one-pot ¹⁸F-fluoroethylation method has developed. • The radiosynthesis of [¹⁸F]FEDAC and [¹⁸F]FET were simplified. • A lower cost of the precursors for ¹⁸F-fluoroethylation is provided. • A shorter synthesis time for ¹⁸F-fluoroethylation is provided. • Automated one-pot ¹⁸F-fluoroethylation strategy is provided. Recently, a straightforward one-pot method for ¹⁸F-fluoroethylation without azeotropic drying of cyclotron-produced [¹⁸F]F⁻ was developed. In this study, we have attempted to simplify the automated radiosynthesis of two [¹⁸F]fluoroethylated tracers, [¹⁸F]FEDAC and [¹⁸F]FET, using a desmethyl labeling precursor and [¹⁸F]fluoroethyl tosylate, based on the above-mentioned method. The radiochemical yields of [¹⁸F]FEDAC and [¹⁸F]FET were 26 ± 3.7% (n = 5) and 14 ± 2.2% (n = 4), respectively, based on total [¹⁸F]F⁻ at the end of irradiation.

[en] Introduction: The aim of this study was to evaluate N-benzyl-N-[¹¹C]methyl-2- (7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl) acetamide ([¹¹C]DAC) as a novel peripheral-type benzodiazepine receptor (PBR) ligand for tumor imaging. Methods: [¹¹C]DAC was synthesized by the reaction of a desmethyl precursor with [¹¹C]CH₃I. In vitro uptake of [¹¹C]DAC was examined in PBR-expressing C6 glioma and intact murine fibrosarcoma (NFSa) cells. In vivo distribution of [¹¹C]DAC was determined using NFSa-bearing mice and small-animal positron emission tomography (PET). Results: [¹¹C]DAC showed specific binding to PBR in C6 glioma cells, a standard cell line with high PBR expression. Specific binding of [¹¹C]DAC was also confirmed in NFSa cells, a target tumor cell line in this study. Results of PET experiments using NFSa-bearing mice, showed that [¹¹C]DAC was taken up specifically into the tumor, and pretreatment with PK11195 abolished the uptake. Conclusions: [¹¹C]DAC was taken up into PBR-expressing NFSa. [¹¹C]DAC is a promising PET ligand that can be used for imaging PBR in tumor-bearing mice.

[en] The aim of this study was how to introduce radioactive chlorine (*Cl) isotope into a benzene ring to afford *Cl-labeled chlorobenzene ([*Cl]1). Using tributylphenylstannyl compound (2) as a starting material, we determined two routes for introducing *Cl into the benzene ring: reaction of [*Cl]Cl^- with 2 in the presence of chloramine-T and nucleophilic reaction of [*Cl]Cl^- with diphenyliodonium tosylate (3). The two routes provide suitable tools to prepare [*Cl]1 without electron-abstracting group in the benzene ring

[en] Introduction: The functions of I_2-imidazoline receptors (I_2Rs) are unknown, but evidence exists for their involvement in various neuropsychiatric disorders. Although a few positron emission tomography (PET) I_2R ligands have been developed, of which ["1"1C]FTIMD and ["1"1C]BU99008 were evaluated as PET I_2R imaging ligands in monkeys, no human PET imaging study using an I_2R-selective PET ligand has been conducted yet. Thus, we synthesized an "1"8F-labeled I_2R-selective ligand (BU99018 or FEBU, Ki for I_2Rs = 2.6 nM), and evaluated its application using rodents in PET imaging in vivo toward the development of a clinically-useful I_2R PET imaging ligand. Methods: ["1"8F]FEBU was synthesized by the reaction of its precursor and ["1"8F]fluoroethyl bromide. A biodistribution and brain PET study were conducted in mice and rats respectively. Results: ["1"8F]FEBU was successfully synthesized yielding a radioactivity suitable for injection (10.1 ± 5.3% at the end of the irradiation (n = 10) based on "1"8F"−). The specific activity at end of synthesis (EOS) was 40–147 TBq/mmol (n = 10). The radiochemical purity was > 99% at EOS and remained > 99% for 90 min after EOS. In mice brain uptake was relatively high. In the blocking study with the co-injection of the high-affinity I_2R ligand BU224 (1 mg/kg b.w.) brain uptake was significantly decreased 30 min post-injection. In the PET studies the radioactivity was highly accumulated in the I_2R-rich hypothalamus. Pretreatment with BU224 (1 mg/kg b.w.) significantly decreased the radioactivity in the hypothalamus to 23% of that of the control from 60 to 90 min post-injection. Conclusion: ["1"8F]FEBU was sufficiently stable as a PET ligand and had a relatively high specific binding affinity for I_2Rs in rats and mice

[en] 

Background

Neuropeptide Y (NPY) has been implicated in a wide variety of physiological processes, including feeding, learning, memory, emotion, cardiovascular homeostasis, hormone secretion, and circadian rhythms. NPY Yl receptor (NPY Y1-R) is the most widely studied NPY receptor, and is involved in many of these processes. BMS-193885 (1) was previously developed as a potent and selective NPY Y1-R antagonist, which has good systemic bioavailability and brain penetration. To evaluate the characteristics of 1 in vivo, we developed ¹¹C-labeled BMS-193885 ([¹¹C]1) and its desmethyl analog ([¹¹C]2) for potential use as two new positron emission tomography (PET) tracers.

Results

[¹¹C]1 was synthesized from [¹¹C]methyl iodide using 2. [¹¹C]2 was synthesized from [¹¹C]phosgene using its aniline and amine derivatives. The mean ± S.D. decay-corrected radiochemical yields of [¹¹C]1 and [¹¹C]2 from ¹¹CO₂ at the end of radionuclide production were 23 ± 3.2% (n = 6) and 24 ± 1.5% (n = 4), respectively. In biodistribution on mice, radioactivity levels for both tracers were relatively high in the kidney, small intestine, and liver at 60 min post-injection. The radioactivity levels in the kidney, lung, and spleen of mice at 30 min post-injection with [¹¹C]1 were significantly reduced by pretreatment with 1 (10 mg/kg), and levels of [¹¹C]1 in the brain of mice were significantly increased by pretreatment with the P-glycoprotein and breast cancer resistance protein inhibitor elacridar (10 mg/kg). In metabolite analysis using mouse plasma, [¹¹C]1 and [¹¹C]2 were rapidly metabolized within 30 min post-injection, and [¹¹C]1 was mainly metabolized into unlabeled 2 and radiolabeled components.

Conclusion

[¹¹C]1 and [¹¹C]2 were successfully synthesized with sufficient amount of radioactivity and high quality for use in vivo. Our study of [¹¹C]1 and its desmethyl analog [¹¹C]2 was useful in that it helped to elucidate the in vivo characteristics of 1.

[en] Introduction: We recently developed a selective ¹¹C-labeled I₂-imidazoline receptor (I₂R) ligand, 2-(3-fluoro-4-[¹¹C]tolyl)-4,5-dihydro-1H-imidazole ([¹¹C]FTIMD). [¹¹C]FTIMD showed specific binding to I₂Rs in rat brains having a high density of I₂R, as well as to I₂Rs those in monkey brains, as illustrated by positron emission tomography (PET) and autoradiography. However, [¹¹C]FTIMD also showed moderate non-specific binding in rat brains. In order to increase the specificity for I₂R in rat brains, we synthesized [¹¹C]FTIMD with ultra-high specific activity and evaluated its binding. Methods: [¹¹C]FTIMD with ultra-high specific activity was prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [¹¹C]methyl iodide, which was produced by iodination of [¹¹C]methane using the single-pass method. Dynamic PET scans were conducted in rats, and the kinetic parameters were estimated. Results: [¹¹C]FTIMD with ultra-high specific activity was successfully synthesized with an appropriate level of radioactivity and ultra-high specific activity (4470±1660 GBq/μmol at end of synthesis, n=11) for injection. In the PET study, distribution volume (V_T) values in all the brain regions investigated whether I₂R expression was greatly reduced in BU224-pretreatead rats compared with control rats (29–45% decrease). Differences in V_T values between control and BU224-pretreated rats using [¹¹C]FTIMD with ultra-high specific activity were greater than those using [¹¹C]FTIMD with normal specific activity (17–34% decrease) in all brain regions investigated. Conclusion: Quantitative PET using [¹¹C]FTIMD with ultra-high specific activity can contribute to the detection of small changes in I₂R expression in the brain.

[en] Introduction: [¹¹C]ABP688 is a promising positron emission tomography (PET) ligand for imaging of metabotropic glutamate receptor subtype 5 (mGlu5 receptor). Of the two geometric isomers of ABP688, (E)-ABP688 has a greater affinity towards mGlu5 receptors than (Z)-ABP688. Therefore, a high ratio of E-isomer is required when using [¹¹C]ABP688 as a PET probe for imaging and quantification of mGlu5 receptors. The aim of this study was to evaluate the effect (Z)-[¹¹C]ABP688 on the synthesis of [¹¹C]ABP688 to be used for binding (E)-[¹¹C]ABP688 in the brain. Methods: We synthesized and separated (E)- and (Z)-[¹¹C]ABP688 by purification using an improved preparative high-performance liquid chromatography (HPLC) method equipped with a COSMOSIL Cholester column. We performed an in vitro binding assay in rat brain homogenates and PET studies of the rat brains using (E)- and (Z)-[¹¹C]ABP688. Results: (E)- and (Z)-[¹¹C]ABP688 were successfully obtained with suitable radioactivity for application. In the in vitro assay, the K_d value of (E)-[¹¹C]ABP688 (5.7 nmol/L) was higher than that of (Z)-[¹¹C]ABP688 (140 nmol/L). In the PET study of the rat brain, high radioactivity after injection of (E)-[¹¹C]ABP688 was observed in regions rich in mGlu5 receptors such as the striatum and hippocampus. In contrast, after injection of (Z)-[¹¹C]ABP688, radioactivity did not accumulate in the brain. Furthermore, BP_ND in the striatum and hippocampus was highly correlated (R² = 0.99) with the percentage of (E)-[¹¹C]ABP688 of the total radioactivity of (E)- and (Z)-[¹¹C]ABP688 in the injection. Conclusion: We demonstrated that including (Z)-[¹¹C]ABP688 in the [¹¹C]ABP688 injection can decrease BP_ND in regions rich in mGlu5 receptors. Routine production of (E)-[¹¹C]ABP688 will be helpful for imaging and quantification of mGlu5 receptors in clinical studies