Effects of structural differences between radioiodine-labeled 1-(2′-fluoro-2′-deoxy-d-arabinofuranosyl)-5-iodouracil (FIAU) and 1-(2′-fluoro-2′-deoxy-d-ribofuranosyl)-5-iodouracil (FIRU) on HSV1-TK reporter gene imaging

The goal of this investigation was to evaluate the effects of structural differences between FIAU and FIRU on their ability to serve as a potential tracer for reporter gene imaging. To examine the characteristics of different configurations of FIAU and FIRU, a series of evaluations were done on HSV1-TK gene-expressing cells and on mice with HSV1-TK gene-expressing tumor. The results showed that, as an imaging agent for HSV1-TK-expressing cells, radiolabeled FIAU was more efficient for in vivo imaging than FIRU.     

Synthesis and biological properties of (E)-5-(2-[82Br]bromovinyl)-1-(2-deoxy-2-fluoro-β-d-ribofuranosyl)uracil ([82Br]BVFRU)

(E)-5-(2-Bromovinyl)-1-(2-deoxy-2-fluoro-β-d-ribofuranosyl)uracil (BVFRU) was synthesized in 24% yield by reacting (E)-5-(2-carboxyvinyl)-1-(2-deoxy-2-fluoro-β-d-ribofuranosyl)uracil (CVFRU) with NH₄Br in the presence of chloramine-T. [⁸²Br]BVFRU was prepared in 14.5% radiochemical yield, with a specific activity of 58 MBq mmol^-1, by a similar reaction of CVFRU with ammonium [⁸²Br]bromide. BVFRU is equipotent to iodovinyldeoxyuridine (IVDU) and iodovinyl-2′-fluorodeoxyuridine (IVFRU) (MIC₅₀ = 0.1–0.01 μ g mL^-1) against herpes simplex virus which encodes for thymidine kinase (HSV-1 TK⁺), and has a partition coefficient similar to that of IVDU and IVFRU (log P = 0.72 vs 1.6 and 1.21, respectively). BVFRU has an inhibition constant (K_i) of 0.044 for the nitrobenzylthioinosine (NBMPR)-sensitive transport of thymidine across the murine erythrocyte membrane. These data suggest that BVFRU is similar to BVDU in antiviral potency and transport characteristics; it is proposed that ease of synthesis and resistance to metabolic degradation make radiolabelled BVFRU a superior candidate for in vivo diagnostic studies of HSE.     

Nicotinic α4β2 receptor imaging agents. Part III. Synthesis and biological evaluation of 3-(2-(S)-azetidinylmethoxy)-5-(3'-18F-fluoropropyl)pyridine (18F-nifzetidine)

Thalamic and extrathalamic nicotinic α4β2 receptors found in the brain have been implicated in Alzheimer's disease, Parkinson's disease, substance abuse and other disorders. We report here the development of 3-(2-(S)-azetidinylmethoxy)-5-(3′-fluoropropyl)pyridine (nifzetidine) as a new putative high-affinity antagonist for nicotinic α4β2 receptors. Nifzetidine in rat brain homogenate assays containing α4β2 sites labeled with ³H-cytisine exhibited a binding affinity: Ki=0.67 nM. The fluorine-18 analog, 3-(2-(S)-azetidinylmethoxy)-5-(3′-¹⁸F-fluoropropyl)pyridine (¹⁸F-nifzetidine), was synthesized in 20%–40% yield, and apparent specific activity was estimated to be above 2 Ci/μmol. Rat brain slices indicated selective binding of ¹⁸F-nifzetidine to thalamus, subiculum, striata, cortex and other regions consistent with α4β2 receptor distribution. This selective binding was displaced >85% by 150 μM nicotine. Positron emission tomography (PET) imaging studies of ¹⁸F-nifzetidine in anesthetized rhesus monkey showed slow uptake in the various brain regions. Retention of ¹⁸F-nifzetidine was maximal in the thalamus and lateral geniculate followed by regions of the temporal and frontal cortex. Cerebellum showed the least uptake. Thalamus to cerebellum ratio was about 2.3 at 180 min postinjection and continued to rise. ¹⁸F-Nifzetidine shows promise as a new PET imaging agent for α4β2 nAChR. However, the slow kinetics suggests a need for >3-h PET scans for quantitative studies of the α4β2 nAChRs.     

Synthesis and evaluation of radioiodinated (S,S)-2-(α-(2-iodophenoxy)benzyl)morpholine for imaging brain norepinephrine transporter

Purpose Abnormality of the brain norepinephrine transporter (NET) has been reported in several psychiatric and neuronal disorders. Since NET is an important target for the diagnosis of these diseases, the development of radiopharmaceuticals for imaging of brain NET has been eagerly awaited. In this study, we synthesized (S,S)-2-(α-(2-iodophenoxy)benzyl)morpholine [(S,S)-IPBM], a derivative of reboxetine iodinated at position 2 of the phenoxy ring, and evaluated its potential as a radiopharmaceutical for imaging brain NET using SPECT.Methods (S,S)-^123/125I-IPBM was synthesized in a halogen exchange reaction. The affinity and selectivity of (S,S)-IPBM for NET was measured by assaying the displacement of ³H-nisoxetine and (S,S)-¹²⁵I-IPBM from the binding site in rat brain membrane, respectively. The biodistribution of (S,S)-¹²⁵I-IPBM was also determined in rats. Furthermore, SPECT studies with (S,S)-¹²³I-IPBM were carried out in the common marmoset.Results (S,S)-¹²⁵I-IPBM was prepared with high radiochemical yields (65%) and high radiochemical purity (>98%). (S,S)-IPBM showed high affinity and selectivity for NET in the binding assay experiments. In biodistribution experiments, (S,S)-¹²⁵I-IPBM showed rapid uptake in the brain, and the regional cerebral distribution was consistent with the density of NET. The administration of nisoxetine, a selective NET-binding agent, decreased the accumulation of (S,S)-¹²⁵I-IPBM in the brain, but the administration of selective serotonin transporter and dopamine transporter binding agents caused no significant changes in the accumulation. Moreover, (S,S)-¹²³I-IPBM allowed brain NET imaging in the common marmoset with SPECT.Conclusion These results suggest that (S,S)-¹²³I-IPBM is a potential SPECT radiopharmaceutical for imaging brain NET.     

Identification and quantitation of two new naphthoylindole drugs-of-abuse, (1-(5-hydroxypentyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone (AM-2202) and (1-(4-pentenyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone, with other synthetic cannabinoids in unregulated “herbal” products circulated in the Tokyo area

During our continual surveillance of unregulated drugs in May–June 2011, we found two new compounds as adulterants in herbal products obtained at shops in the Tokyo area. These compounds were identified by liquid chromatography–mass spectrometry, gas chromatography–mass spectrometry, accurate mass spectrometry, and nuclear magnetic resonance spectroscopy. The first compound identified was a naphthoylindole (1-(5-hydroxypentyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone (AM-2202, 1), which is a side-chain hydroxyl analogue of JWH-018. The second compound was (1-(4-pentenyl)-1H-indol-3-yl)(naphthalen-1-yl)methanone (2), which is side-chain double bond analogue of JWH-018. This is the first report to identify 1 and 2 in a commercial “herbal” product to our knowledge. For quantitation of the above compounds 1 and 2, and chemical analysis for previously reported compounds (AM-2201, 3; JWH-203, 4; JWH-019, 7; JWH-210, 8; mitragynine, 9), each product was extracted with methanol under ultrasonication to prepare solutions for analysis by liquid chromatography with ultraviolet detection. For the sake of identifying JWH-203 (4) and its positional isomers [JWH-203-3-chloroisomer (5) and 4-chloroisomer (6)] correctly, simultaneous liquid chromatography analysis on fluorocarbon-bonded silica gel column was performed. And a case report of commercially available products containing synthetic cannabinoids 7 and 8, and a natural occurring alkaloid 9, was also shown. Each of 6 commercially circulated products contained compounds 1–4 and 7–9; the amounts of the compounds ranged from 4.1 to 222 mg per pack.     

Radiosynthesis and ex vivo evaluation of (R)-(−)-2-chloro-N-[1-11C-propyl]n-propylnorapomorphine

IntroductionSeveral dopamine D₂ agonist radioligands have been used with positron emission tomography (PET), including [¹¹C-]-(?)-MNPA, [¹¹C-]-(?)-NPA and [¹¹C]-(+)-PHNO. These radioligands are considered particularly powerful for detection of endogenous dopamine release, but they either provide PET brain images with limited contrast or have affinity for both D₂ and D₃ receptors. We here present the carbon-11 radiolabeling and ex vivo evaluation of 2-Cl-(?)-NPA, a novel PET-tracer candidate with high in vitro D₂/D₃ selectivity.Methods2-Cl-[¹¹C]-(?)-NPA and [¹¹C]-(?)-NPA were synthesized by a two step N-acylation-reduction process using [¹¹C]-propionyl chloride. Awake rats were injected with either tracer, via the tail vein. The rats were decapitated at various times, the brains were removed and quickly dissected, and plasma metabolites were measured. Radioligand specificity, and P-glycoprotein involvement in brain uptake, was also assessed.Results2-Cl-[¹¹C]-(?)-NPA and [¹¹C]-(?)-NPA were produced in high specific activity and purity. 2-Cl-[¹¹C]-(?)-NPA accumulated slower in the striatum than [¹¹C]-(?)-NPA, reaching maximum concentrations after 30 min. The maximal striatal uptake of 2-Cl-[¹¹C]-(?)-NPA (standard uptake value 0.72±0.24) was approximately half that of [¹¹C]-(?)-NPA (standard uptake value 1.37±0.18). Nonspecific uptake was similar for the two compounds. 2-Cl-[¹¹C]-(?)-NPA was metabolized quickly, leaving only 17% of the parent compound in the plasma after 30 min. The specific binding of 2-Cl-[¹¹C]-(?)-NPA was completely blocked and inhibition of P-glycoprotein did not alter the brain uptake.ConclusionEx vivo experiments showed, despite a favorable D₂/D₃ selectivity, that 2-Cl-[¹¹C]-(?)-NPA is inferior to [¹¹C]-(?)-NPA as a PET tracer in rat, because of slower brain uptake and lower specific to nonspecific binding ratio.     

Fluorinated benzamide neuroleptics—2. Synthesis and radiosynthesis of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-3-substituted-2-methoxybenzamides

Synthesis of a fluorinated benzamide neuroleptic, (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3-fluoropropyl)-2,3-dimethoxybenzamide starting from 3-(3,4-dimethoxyphenyl)-1-propanol in 20–25% overall yield is reported. Radiosynthesis of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3[¹⁸F]fluoropropyl)-2-methoxybenzamide([¹⁸F]FPHB) and (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3[¹⁸F]fluoropropyl)-2,3-dimethoxybenzamide([¹⁸F]FPHB) was carried out by nucleophilic substitution reaction of (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl-5-(3-tosyloxypropyl)-2-methoxybenzamide and (S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(3-tosyloxypropyl)-2,3-dimethoxybenzamide respectively, with no carrier added [¹⁸F]fluoride. Both, [¹⁸F]FPHB and [¹⁸F]FPHB were obtained in approx. 20–30% yields (EOS/EOB, decay corrected). Specific activities of 900–1700 Ci/mmol for [¹⁸F]FPHB and 800–1400 Ci/mmol for [¹⁸F]FPMB were obtained by reverse phase HPLC purification. Total synthesis and purification time required for either [¹⁸F]FPHB or [¹⁸F]FPMB was 120 min from EOB.     

Herpes simplex virus thymidine kinase imaging in mice with (1-(2′-deoxy-2′-[<Superscript>18</Superscript>F]fluoro-1-β-D-arabinofuranosyl)-5-iodouracil) and metabolite (1-(2′-deoxy-2′-[<Superscript>18</Superscript>F]fluoro-1-β-D-arabinofuranosyl)-5-uracil)

Purpose  

FIAU, (1-(2′-deoxy-2′-fluoro-1-β-D-arabinofuranosyl)-5-iodouracil) has been used as a substrate for herpes simplex virus thymidine kinases (HSV-TK and HSV-tk, for protein and gene expression, respectively) and other bacterial and viral thymidine kinases for noninvasive imaging applications. Previous studies have reported the formation of a de-iodinated metabolite of ¹⁸F-FIAU. This study reports the dynamic tumor uptake, biodistribution, and metabolite contribution to the activity of ¹⁸F-FIAU seen in HSV-tk gene expressing tumors and compares the distribution properties with its de-iodinated metabolite ¹⁸F-FAU.     

有效的辐射致敏剂——4(5)-碘-5(4)-硝基咪唑衍生物

本文报道了一系列4(5)-碘-5(4)-硝基咪唑衍生物的合成路线和辐射致敏效力。在任何情况下,4(5)-碘-5(4)-硝基咪唑与1,2-环氧-3-甲氧基丙烷或α-氯代乙酸乙酯反应,分别得到两个异构体,结构由NMR 光谱确定。乙基酯和3-吡啶甲胺反应,得到相应的酰胺。5-碘-4-硝基咪唑     

Comparison of iodine-123 labelled 2β-carbomethoxy-3β-(4-iodophenyl)tropane and 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane for imaging of the dopamine transporter in the living human brain

Several cocaine congeners are of potential for imaging the dopamine transporter (DAT). Previous studies have shown that iodine-123 labelled 2-carbomethoxy-3-(4-iodophenyl)tropane ([¹²³I]-CIT) is a promising radiotracer for imaging the serotonin (5-HT) and dopamine (DA) transporters in the living human brain with single-photon emission tomography (SPET). [¹²³I]-CIT was found to be not very practical for 1-day DAT imaging protocols since peak DAT uptake occurs later than 8 h. Here we report a pilot comparison of [¹²³I]-CIT and 2-carbomethoxy-3-(4-iodophenyl)-N-(3-fluoropropyl)nortropane ([¹²³I]-CIT FP), using SPET imaging in four healthy male subjects. Peak uptake of [¹²³I]-CIT-FP into the basal ganglia occurred earlier (3–4 h after injection of tracer) than that of [¹²³I]-CIT (>8 h). However, the specific DAT binding of [¹²³I]-CIT-FP in the basal ganglia was somewhat less (0.813±0.047) than that of [¹²³I]-CIT (0.922±0.004). Imaging quality is excellent with both tracers and they are potentially of value for brain imaging in various neuropsychiatric disorders.     

α-〔〔(2-卤乙基)氨基〕甲基〕-2-硝基-1H-咪唑-1-乙醇作为α-〔(1-氮丙啶)甲基)-2-硝基-1H-咪唑-1-乙醇(RSU-1069)的药物前体和它的类似物的化学合成及其辐射增敏与生物还原细胞毒素活性的评价

RSU-1069在离体与整体试验中都表明它是乏氧细胞辐射增敏和生物还原细胞毒性物,但在Ⅰ期试验中观察到毒性较大,为此,合成了一系列稳定的RSU-1069衍生物.它们的主要化学结构如下:     

用1-苯基-3-甲基-4-苯甲酰吡喹啉酮-5(PMBP)从磷酸溶液中苯取铀(Ⅳ)

本文论述了用萃取-分光光度法测定磷酸溶液中铀的含量,对此,研究过几种技术,其中适用于低铀含量(0.02～0.2g/l)的方法之一是以二(2-乙基己基)磷酸(DEHPA)和三辛基氧化膦(TOPO)协同萃取铀(Ⅵ)为基础,经反萃后用偶氮胂Ⅲ进行比色测定。用1-苯基-3-甲基-4-0苯甲酰吡唑啉酮-5(PMBP)萃取铀Ⅵ尚未研究过。但据锕系元素萃取行为的相似性来推测,可望获得较好的萃取率。另一方面,PMBP的酸性强于噻吩甲酰三氟丙酮(TTA),     

Identification and quantitation of a benzoylindole (2-methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone and a naphthoylindole 1-(5-fluoropentyl-1H-indol-3-yl)-(naphthalene-1-yl)methanone (AM-2201) found in illegal products obtained via the Internet and their cannabimimetic effects evaluated by in vitro [35S]GTP��S binding assays

During our careful surveillance of unregulated drugs in January to February 2011, we found two new compounds used as adulterants in herbal products obtained via the Internet. These compounds were identified by liquid chromatography?Cmass spectrometry, gas chromatography-mass spectrometry, accurate mass spectrometry, and nuclear magnetic resonance spectroscopy. The first compound identified was a benzoylindole (2-methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone (1), which is a positional isomer of (4-methoxyphenyl)(1-pentyl-1H-indol-3-yl)methanone (RCS-4, 4). The second compound was 1-(5-fluoropentyl-1H-indol-3-yl)-(naphthalene-1-yl)methanone (AM-2201, 2). The compound 2 has been reported to be a cannabinoid receptor agonist. Because the cannabimimetic effects of compounds 1 and 4 have not been reported to date, their biological activities were evaluated by measuring the activation of [³⁵S] guanosine-5??-O-(3-thio)-triphosphate binding to guanine nucleotide-binding proteins, together with those of other synthetic cannabimimetic compounds. For quantitation of the above two compounds (1 and 2) and previously identified compounds (AM-694, 3; JWH-122, 5; RCS-4, 4), each product was extracted with methanol under ultrasonication to prepare a sample solution for analysis by liquid chromatography with ultraviolet detection. Each of four commercial products contained some of cannabimimetic indoles 1?C5; their contents ranged from 14.8 to 185 mg per pack.     

用1-苯基-3-甲基-4-苯甲酰吡唑啉酮-5(PMBP)从磷酸溶液中苯取铀(Ⅳ)

本文论述了用萃取-分光光度法测定磷酸溶液中铀的含量,对此,研究过几种技术,其中适用于低铀含量(0.02~0.2g/l)的方法之一是以二(2-乙基己基)磷酸(DEHPA)和三辛基氧化膦(TOPO)协同萃取铀(Ⅵ)为基础,经反萃后用偶氮胂Ⅲ进行比色测定。     

一种新的钌增敏剂——二氯化钌(二甲基亚砜)_2(4-硝基咪唑)_2

硝基咪唑类化合物作为辐射增敏剂,因限定剂量的副作用,在临床上妨碍了增敏作用的充分发挥。理想的目标是降低辐射增敏剂的总浓度,以减少副作用,而在离子辐射损伤的靶子上保持高的药物浓度。为此,可把辐射增敏剂接在与DNA结合的某种金属上,即把该金属作为辐射增敏剂的载体,从而可提高靶上的药物浓度,以增强辐射增敏作用。早期研究抗肿瘤的钌复合物——顺式二氯化钌(二甲基亚砜)_4与DNA结合的机制,类似于临床上成功应用的铂复合物——顺式-二氨基(二氯)铂(Ⅱ)。