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.     

Two new synthetic cannabinoids, AM-2201 benzimidazole analog (FUBIMINA) and (4-methylpiperazin-1-yl)(1-pentyl-1H-indol-3-yl)methanone (MEPIRAPIM), and three phenethylamine derivatives, 25H-NBOMe 3,4,5-trimethoxybenzyl analog, 25B-NBOMe, and 2C-N-NBOMe, identified in illegal products

Two new types of synthetic cannabinoids, an AM-2201 benzimidazole analog (FUBIMINA, 1) and (4-methylpiperazin-1-yl)(1-pentyl-1H-indol-3-yl)methanone (MEPIRAPIM, 2), and three newly emerged phenethylamine derivatives, 25B-NBOMe (3), 2C-N-NBOMe (4), and a 25H-NBOMe 3,4,5-trimethoxybenzyl analog (5), were detected in illegal products distributed in Japan. The identification was based on liquid chromatography–mass spectrometry (LC–MS) and gas chromatography–mass spectrometry (GC–MS), high-resolution MS, and nuclear magnetic resonance analyses. Different from the representative synthetic cannabinoids, such as JWH-018, which have a naphthoylindole moiety, compounds 1 and 2 were completely new types of synthetic cannabinoids; compound 1 had a benzimidazole group in place of an indole group, and compound 2 had a 4-methylpiperazine group in place of the naphthyl group. Compounds 3 and 4 were N-o-methoxybenzyl derivatives of 2,5-dimethoxyphenethylamines (25-NBOMe series), which had been previously detected in European countries, but have newly emerged in Japan. Compound 5 had an N-trimethoxybenzyl group in place of an N-o-methoxybenzyl group. Data on the chemistry and pharmacology of compounds 1, 2, and 5 have never been reported to our knowledge.     

New cannabimimetic indazole derivatives, N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (AB-PINACA) and N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide (AB-FUBINACA) identified as designer drugs in illegal products

Two new cannabimimetic indazole derivatives, N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-pentyl-1H-indazole-3-carboxamide (AB-PINACA, 1) and N-(1-amino-3-methyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide (AB-FUBINACA, 2), have been identified as designer drugs in illegal products. These identifications were based on liquid chromatography–mass spectrometry, gas chromatography–mass spectrometry, high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy. Because there have been neither chemical nor pharmacological data about compound 1 until now, this is the first report of this compound. Compound 2 was reported as a potent cannabinoid CB₁ receptor modulator when synthesized by Pfizer in 2009; but this is the first report of its detection in illegal products.     

Analysis of azepane isomers of AM-2233 and AM-1220, and detection of an inhibitor of fatty acid amide hydrolase [3′-(aminocarbonyl)(1,1′-biphenyl)-3-yl]-cyclohexylcarbamate (URB597) obtained as designer drugs in the Tokyo area

During our careful survey of unregulated drugs from November 2011 to January 2012 in the Tokyo area, we found two new compounds in commercial products. The first was identified as the benzoylindole (2-iodophenyl)[1-(1-methylazepan-3-yl)-1H-indol-3-yl]methanone (2), which is the azepane isomer of AM-2233 (1). Compound 2 was isolated by silica gel column chromatography, and was identified through a combination of liquid chromatography–mass spectrometry, gas chromatography–mass spectrometry, accurate mass spectrometry, and nuclear magnetic resonance spectroscopy. The second compound was identified as [3′-(aminocarbonyl)(1,1′-biphenyl)-3-yl]-cyclohexylcarbamate (URB597, 5) by comparing analytical data with that of the authentic compound. For quantitation of these three compounds, each commercial product was extracted with methanol under ultrasonication to prepare the solution for analysis by liquid chromatography with ultraviolet detection. The occurrence of compounds 1 and 2, and AM-1220 (3) and its azepane isomer (4) in 29 commercial products found in the Tokyo area are also shown in this report.     

Two new-type cannabimimetic quinolinyl carboxylates, QUPIC and QUCHIC, two new cannabimimetic carboxamide derivatives, ADB-FUBINACA and ADBICA, and five synthetic cannabinoids detected with a thiophene derivative α-PVT and an opioid receptor agonist AH-7921 identified in illegal products

We identified two new-type cannabimimetic quinolinyl carboxylates, quinolin-8-yl 1-pentyl-(1H-indole)-3-carboxylate (QUPIC, 1) and quinolin-8-yl 1-(cyclohexylmethyl)-1H-indole-3-carboxylate (QUCHIC, 2); and two new cannabimimetic carboxamide derivatives, N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-(4-fluorobenzyl)-1H-indazole-3-carboxamide (ADB-FUBINACA, 3) and N-(1-amino-3,3-dimethyl-1-oxobutan-2-yl)-1-pentyl-1H-indole-3-carboxamide (ADBICA, 4), as designer drugs in illegal products. Compound 3 was reported to have a potent affinity for cannabinoid CB₁ receptor by Pfizer in 2009, but this is the first report of its detection in illegal products. No chemical or pharmacological data for compounds 1, 2, and 4 have appeared until now, making this the first report on these compounds. We also detected synthetic cannabinoids, APICA N-(5-fluoropentyl) analog (5), APINACA N-(5-fluoropentyl) analog (6), UR-144 N-(5-chloropentyl) analog (7), JWH-122 N-(5-chloropentyl) analog (8), and AM-2201 4-methoxynaphthyl analog (4-MeO-AM-2201, 9) herein as newly distributed designer drugs in Japan. It is of interest that compounds 1 and 2 were detected with their synthetic component, 8-quinolinol (10). A stimulant thiophene analog, α-pyrrolidinovalerothiophenone (α-PVT, 11), and an opioid receptor agonist, 3,4-dichloro-N-([1-(dimethylamino)cyclohexyl]methyl)benzamide (AH-7921, 12), were also detected as new types of designer drugs coexisting with several synthetic cannabinoids and cathinone derivatives in illegal products.     

Identification of two new-type designer drugs, piperazine derivative MT-45 (I-C6) and synthetic peptide Noopept (GVS-111), with synthetic cannabinoid A-834735, cathinone derivative 4-methoxy-α-PVP, and phenethylamine derivative 4-methylbuphedrine from illegal products

We identified two new-type designer drugs, piperazine derivative MT-45 [1-cyclohexyl-4-(1,2-diphenylethyl)piperazine, synonym: I-C6, 1] and synthetic peptide Noopept [ethyl 2-(1-(2-phenylacetyl)pyrrolidine-2-carboxamido)acetate, synonym: GVS-111, 2], in chemical and herbal products. MT-45 (1) was previously reported as an opiate-like analgesic substance, and Noopept (2) was reported to have nootropic (cognitive enhancer) activity. We also detected two synthetic cannabinoids, A-834735 (3) and QUPIC N-(5-fluoropentyl) analog (synonym: 5-fluoro-PB-22, 4), in the illegal products. A-834735 (3) was previously reported to act as an agonist at both cannabinoid CB₁ and CB₂ receptors. In addition, cathinone derivative 4-methoxy-α-pyrrolidinovalerophenone (4-methoxy-α-PVP, 5) and phenethylamine derivative 4-methylbuphedrine (6) were newly detected with known cathinone derivative 4-methylbuphedrone (7) in the products.     

Funktioelle Magnetresonanztomographie in Diagnostik und Therapiemonitoring beim Multiplen Myelom

Aim of the study. Investigation of the quantitative microcirculation parameters amplitude A and exchange rate constant k ₂₁ determined by contrast-enhanced dynamic magnetic resonance imaging (d-MRI) in multiple myeloma (MM). Methods. d-MRT of lumbar spine and right spina iliaca superior posterior of 16 controls (ctr) and 35 patients with active MM. Generation of colour-coded images of microcirculation parameters superimposed onto static MRI images. Results. Amplitude A and k ₂₁ parameters were significantly increased in patients with MM and down modulated by therapy in 7 of 8 MM cases in a follow-up investigation [p<0.01; median A _ctr =0.2 (0.09–0.4); median A _MM =0.93 (0.2–1.52); median k _21ctr =0.09 min^–1 (0.03–0.9); median k _21MM =4.57 min^–1 (0.21–23.8)]. Thirteen patients revealed a “diffuse” and 22 a “focal” pattern of distribution of microcirculation parameters. Bone marrow biopsies in 8 cases revealed an correlation between bone marrow plasma cell infiltration and increased microcirculation parameters. Conclusion. Identification of microcirculation changes by d-MRI is a novel imaging technique for the detection and monitoring of MM bone lesions.     

Chemical analysis of a benzofuran derivative, 2-(2-ethylaminopropyl)benzofuran (2-EAPB), eight synthetic cannabinoids,five cathinone derivatives,and five other designer drugs newly detected in illegal products

From November 2013 to May 2014, 19 newly distributed designer drugs were identified in 104 products in our ongoing survey of illegal products in Japan. The identified compounds included 8 synthetic cannabinoids, FUB-PB-22 (1), 5-fluoro-NNEI indazole analog (5-fluoro-MN-18, 2), AM-2201 indazole analog (THJ-2201, 3), XLR-12 (4), 5-fluoro-AB-PINACA (5), 5-chloro-AB-PINACA (6), AB-CHMINACA (7), and 5-fluoro-AMB (8); 5 cathinone derivatives, DL-4662 (9), α-PHP (10), 4-methoxy-α-POP (11), 4-methoxy-α-PHPP (12), and 4-fluoro-α-PHPP (13); and 6 other substances, namely, the benzofuran derivative 2-(2-ethylaminopropyl)benzofuran (2-EAPB, 14), nitracaine (15), diclofensine (16), diphenidine (17), 1-benzylpiperidine (18), and acetylfentanyl (19). To our knowledge, this is the first report on the chemical properties of compounds 9–11 and 14. A total of 33 designer drugs, including compounds 1–19, were detected in the 104 illegal products, in 60 different combination patterns. The numbers of detected compounds per product ranged from 1 to 7. In addition, several products contained three different types of compounds, such as synthetic cannabinoids, cathinone derivatives, and phenethylamine derivatives per product. It is apparent that the types of compounds emerging as illegal products are becoming more diverse, as are their combinations.     

Preclinical evaluation of BAY 1075553, a novel 18F-labelled inhibitor of prostate-specific membrane antigen for PET imaging of prostate cancer

Purpose

Prostate-specific membrane antigen (PSMA) is a transmembrane protein overexpressed in prostate cancer and is therefore being explored as a biomarker for diagnosing and staging of the disease. Here we report preclinical data on BAY 1075553 (a 9:1 mixture of (2S,4S)- and (2R,4S)-2-[¹⁸F]fluoro-4-phosphonomethyl-pentanedioic acid), a novel ¹⁸F-labelled small molecule inhibitor of PSMA enzymatic activity, which can be efficiently synthesized from a direct radiolabelling precursor.

Methods

The ¹⁸F-radiolabelled stereoisomers of 2-[¹⁸F]fluoro-4-(phosphonomethyl)-pentanedioic acid were synthesized from their respective isomerically pure precursors dimethyl 2-{[bis(benzyloxy)phosphoryl]methyl}-4-(tosyloxy)pentanedioate. In vivo positron emission tomography (PET) imaging and biodistribution studies were conducted in mice bearing LNCaP, 22Rv1 and PC-3 tumours. Pharmacokinetic parameters and dosimetry estimates were calculated based on biodistribution studies in rodents. For non-clinical safety assessment (safety pharmacology, toxicology) to support a single-dose human microdose study, off-target effects in vitro, effects on vital organ functions (cardiovascular in dogs, nervous system in rats), mutagenicity screens and an extended single-dose study in rats were conducted with the non-radioactive racemic analogue of BAY 1075553.

Results

BAY 1075553 showed high tumour accumulation specific to PSMA-positive tumour-bearing mice and was superior to other stereoisomers tested. Fast clearance of BAY 1075553 resulted overall in low background signals in other organs except for high uptake into kidney and bladder which was mainly caused by renal elimination of BAY 1075553. A modest uptake into bone was observed which decreased over time indicating organ-specific uptake as opposed to defluorination of BAY 1075553 in vivo. Biodistribution studies found highest organ doses for kidneys and the urinary bladder wall resulting in a projected effective dose (ED) in humans of 0.0219 mSv/MBq. Non-clinical safety studies did not show off-target activity, effects on vital organs function or dose-dependent adverse effects.

Conclusion

BAY 1075553 was identified as a promising PET tracer for PSMA-positive prostate tumours in preclinical studies. BAY 1075553 can be produced using a robust, direct radiosynthesis procedure. Pharmacokinetic, toxicology and safety pharmacology studies support the application of BAY 1075553 in a first-in-man microdose study with single i.v. administration.     

Chemical constituents and DNA sequence analysis of a psychotropic herbal product

In recent years, the distribution of a variety of psychotropic products, especially “spice” and “herbal blends,” which are advertised to have narcotic-like effects, has become more widespread in the Japanese illegal drug market. We recently found two synthetic annabinoids, cannabicyclohexanol and JWH-018, that serve as adulterants in herbal products purchased via the Internet. In this study, we focused on a herbal product being sold as incense, which showed unknown components by liquid chromatography-mass spectrometry (LC-MS). The product did not show any peak corresponding to the above synthetic cannabinoids, but seven other peaks were identified by high-performance liquid chromatography and LC-MS. We identified them as N-methyltyramine (1), (R)-normacromerine (2), (R)-macromerine (3), (S)-vasicine (4), mescaline (5), harmaline (6), and harmine (7) by polarimetry, LC-MS, gas chromatography-mass spectrometry, high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy. We also used DNA sequence analyses to identify the plant species of the product. As a result of the sequencing of trnL-F, internal transcribed spacer (ITS), and rpl16 intron regions, three sequences derived from Coryphantha macromeris (Cactaceae), Peganum harmala (Zygophyllaceae), and Turnera diffusa (Turneraceae) were observed. Compounds 2 and 3, both phenethylamines, were reported to cause hallucinogenic effects and are frequently found in Coryphantha genus (Cactaceae). Therefore, the plant source of these compounds was considered to be C. macromeris. Compound 5 is known to be a psychoactive phenethylamine found in peyote (Lophophora williamsii) and San Pedro cactus (Trichocereus pachanoi). The β-carboline alkaloids 6 and 7 are known to be found in the seeds of P. harmala. Therefore, there seems to be no contradiction between the chemical constituents and the plant species estimated by DNA analyses, except for compound 5. This is the first report dealing with identification of the psychoactive cactus C. macromeris and its constituent compounds in a herbal product distributed in the illegal drug market.     

18F-FDG PET/CT is a valuable tool for relapsing polychondritis diagnose and therapeutic response monitoring

Objectives

To retrospectively investigate the role of ¹⁸ F–fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) for the diagnosis and therapeutic response in relapsing polychondritis (RP) patients.

Methods

¹⁸F-FDG PET/CT findings were reviewed in six RP patients. The initial scans were performed for all patients, follow-up scans were performed during steroid therapy for five patients. Changes in the abnormal lesions and the maximal standard uptake value (SUV_max) were analyzed.

Results

The initial PET/CT scans revealed intense FDG uptake in the cartilages for all six patients. The lesions of abnormal FDG uptake were tracheal/bronchial cartilage (n = 4), costicartilage (n = 4), nasal cartilage (n = 3), cricoid cartilage (n = 3), auricular cartilage (n = 3), arytenoid cartilage (n = 3), thyroid cartilage (n = 2), hyoid cartilage (n = 1) and mediastinum lymph node (n = 1). The mean visual score and the mean SUV_max were 2.96 ± 0.20 and 4.10 ± 0.6. The intense uptake reduced or disappeared during steroid therapy for five patients, the mean visual score and the mean SUV_max were 1.58 ± 1.4 and 1.51 ± 1.4.

Conclusions

¹⁸F-FDG PET/CT enables the acquisition of both morphologic and glucose metabolic of the related cartilage structures. It plays a valuable role in assessing almost all cartilage and detecting RP, which is a better selection of a biopsy site as well as therapeutic response monitoring.     

Dual molecular imaging for targeting metalloproteinase activity and apoptosis in atherosclerosis: molecular imaging facilitates understanding of pathogenesis

Background

Macrophage apoptosis and MMP activity contribute to vulnerability of atherosclerotic plaques to rupture. By employing molecular imaging techniques, we investigated if apoptosis and MMP release are interlinked.

Methods

Atherosclerosis was produced in rabbits receiving high-cholesterol diet (HC), who underwent dual radionuclide imaging with ^99mTc-labeled matrix metalloproteinase inhibitor (MPI) and ¹¹¹In-labeled annexin A5 (AA5) using micro-SPECT/CT. %ID/g MPI and AA5 uptake was measured, followed by histological characterization. Unmanipulated animals were used as disease controls. Correlation between MPI and AA5 uptake was undertaken and relationship confirmed in culture study of activated THP-1 monocytes.

Results

MPI and AA5 uptake was best visualized in HC diet animals (n = 6) and reduced significantly after fluvastatin treatment (n = 4) or diet withdrawal (n = 3). %ID/g MPI (.087 ± .018%) and AA5 (.03 ± .01%) uptake was higher in HC than control (n = 6) animals (.014 ± .004%, P < .0001; .0007 ± .0002%, P < .0001), and reduced substantially after diet or statin intervention. There was a significant correlation between MPI and AA5 uptake (r = .62, P < .0001), both correlated with pathologically verified MMP-9 activity, macrophage content, and TUNEL staining. In vitro studies demonstrated MMP-9 release in culture medium from apoptotic THP-1 monocytes.

Conclusions

The present study suggests that apoptosis and MMP are interrelated in atherosclerotic lesions and the targeting of more than one molecular candidate is feasible by molecular imaging.     

Locally advanced rectal cancer: diffusion-weighted MR tumour volumetry and the apparent diffusion coefficient for evaluating complete remission after preoperative chemoradiation therapy

Objective

To evaluate DW MR tumour volumetry and post-CRT ADC in rectal cancer as predicting factors of CR using high b values to eliminate perfusion effects.

Methods

One hundred rectal cancer patients who underwent 1.5-T rectal MR and DW imaging using three b factors (0, 150, and 1,000 s/mm²) were enrolled. The tumour volumes of T2-weighted MR and DW images and pre- and post-CRT ADC_150–1000 were measured. The diagnostic accuracy of post-CRT ADC, T2-weighted MR, and DW tumour volumetry was compared using ROC analysis.

Results

DW MR tumour volumetry was superior to T2-weighted MR volumetry comparing the CR and non-CR groups (P?<?0.001). Post-CRT ADC showed a significant difference between the CR and non-CR groups (P?=?0.001). The accuracy of DW tumour volumetry (A_z?=?0.910) was superior to that of T2-weighed MR tumour volumetry (A_z?=?0.792) and post-CRT ADC (A_z?=?0.705) in determining CR (P?=?0.015). Using a cutoff value for the tumour volume reduction rate of more than 86.8 % on DW MR images, the sensitivity and specificity for predicting CR were 91.4 % and 80 %, respectively.

Conclusion

DW MR tumour volumetry after CRT showed significant superiority in predicting CR compared with T2-weighted MR images and post-CRT ADC.

Key Points

? Diffusion-weighted MR (DWMR) imaging offers new information about rectal cancer. ? DWMR helps to predict complete remission after chemoradiotherapy in patients with advanced rectal cancer. ? DWMR provides more accurate diagnostic information than T2-weighted MRI. ? Apparent diffusion coefficients can predict CR, but they have certain clinical limitations.     

Wertigkeit der diffusionsgewichteten MRT in der Beurteilung von Knochenmarkveränderungen bei Wirbelkörpermetastasen

Aim of the study. The aim of the study was the evaluation of the diffusion coefficient (ADC) of vertebral metastasis and regular vertebral bodies with diffusion weighted MRI (DWI). DWI evaluates the tissue-specific molecular diffusion of protons. In tissues with high cell densities (neoplasm) a decreased ADC can be expected due to restricted diffusion according to an exaggerated amount of intra- and intercellular membranes (i. e. diffusion barriers). Methods. In 5 breast cancer patients the ADC of both known vertebral metastases and of adjacent regular vertebral bodies were measured with DWI (1.0 T; Phased-Array-Body-Coil; b: 880 and 440 s/mm²). Results. The ADC of regular vertebral bodies (1.3±0.23×10^–,3s/mm²) was significantly (p≤0.0002) higher than in vertebral metastases (0.39±0.11×10^–3s/mm²). Conclusions. These data demonstrate that the ADC can be reliably measured in vertebral bodies. The quantitative evaluation of the ADC in vertebral bodies seems to be an objective and comparable parameter for differentiating malign from benign vertebral tissue.     

Imaging with radiolabelled anti-membrane type 1 matrix metalloproteinase (MT1-MMP) antibody: potentials for characterizing atherosclerotic plaques

Purpose

Membrane type 1 matrix metalloproteinase (MT1-MMP) activates pro-MMP-2 and pro-MMP-13 to their active forms and plays important roles in the destabilization of atherosclerotic plaques. This study sought to determine the usefulness of ^99mTc-labelled monoclonal antibody (mAb), recognizing MT1-MMP, for imaging atherosclerosis in a rabbit model (WHHLMI rabbits).

Methods

Anti-MT1-MMP monoclonal IgG₃ and negative control IgG₃ were radiolabelled with ^99mTc after derivatization with 6-hydrazinonicotinic acid (HYNIC) to yield ^99mTc-MT1-MMP mAb and ^99mTc-IgG₃, respectively. WHHLMI and control rabbits were injected with these radio-probes. The aorta was removed and radioactivity was measured at 24 h after the injection. Autoradiography and histological studies were performed.

Results

^99mTc-MT1-MMP mAb accumulation in WHHLMI rabbit aortas was 5.4-fold higher than that of control rabbits. Regional ^99mTc-MT1-MMP mAb accumulation was positively correlated with MT1-MMP expression (r?=?0.59, p?<?0.0001), while ^99mTc-IgG₃ accumulation was independent of MT1-MMP expression (r?=?0.03, p?=?NS). The highest ^99mTc-MT1-MMP mAb accumulation was found in atheromatous lesions (4.8?±?1.9, %ID×BW/mm²?×?10²), followed in decreasing order by fibroatheromatous (1.8?±?1.3), collagen-rich (1.6?±?1.0) and neointimal lesions (1.5?±?1.5). In contrast, ^99mTc-IgG₃ accumulation was almost independent of the histological grade of lesions.

Conclusion

Higher ^99mTc-MT1-MMP mAb accumulation in grade IV atheroma was shown in comparison with neointimal lesions or other more stable lesions. Nuclear imaging with ^99mTc-MT1-MMP mAb, in combination with CT and MRI, could provide new diagnostic imaging capabilities for detecting vulnerable plaques, although further investigations to improve target to blood ratios are strongly required.     

Identification of the synthetic cannabinoid <Emphasis Type="Italic">N</Emphasis>-(2-phenyl-propan-2-yl)-1-(4-cyanobutyl)-1<Emphasis Type="Italic">H</Emphasis>-indazole-3-carboxamide (CUMYL-4CN-BINACA) in a herbal mixture product

We were the first to detect N-(2-phenylpropan-2-yl)-1-(4-cyanobutyl)-1H-indazole-3-carboxamide (common name CUMYL-4CN-BINACA) as a new synthetic cannabinoid, on the illegal market in Bursa, Turkey. To elucidate the chemical structure, the dried herbal mixture was extracted with methanol. The extract was purified by column chromatography. Pure compound was analyzed by gas chromatography–mass spectrometry (GC–MS), attenuated total reflection Fourier-transform infrared spectroscopy (FT-IR), and one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy. The GC–MS, FT-IR and ¹H and ¹³C NMR spectra of the compound coincided well with the reference data. All protons and carbons were assigned by their couplings and correlations observed in ¹H-¹H correlation spectroscopy, ¹H-¹³C heteronuclear multiple bond correlation, and ¹H-¹³C heteronuclear single quantum coherence spectra. On the basis of the spectral data, the compound was identified as CUMYL-4CN-BINACA. Herewith, we report analytical characteristics of CUMYL-4CN-BINACA enabling its (and possible analogues thereof) determination in criminal seizures.     

Cerebral vein changes in relapsing-remitting multiple sclerosis demonstrated by three-dimensional enhanced T 2 * -weighted angiography at 3.0 T

Objective

To investigate characteristics of the internal cerebral veins (ICVs) and their main tributaries and the deep medullary veins (DMVs) in patients with relapsing-remitting MS (RRMS) with enhanced T ₂ ^* -weighted angiography imaging (ESWAN).

Methods

Fifty-three RRMS patients and 53 normal controls underwent conventional MRI and ESWAN. ESWAN venograms were created by performing minimum intensity projections of the phase images, and the resulting venograms were used to observe characteristic vascular changes, including scores of the ICVs and their main tributaries and manifestations of the DMVs. Two experienced radiologists analysed all data.

Results

Patients showed decreased mean scores of the ICVs and their main tributaries compared with controls. The mean score in acute patients was higher than in stable patients. Furthermore, the DMVs diminished and shortened in 48 patients with longer disease duration, whereas the DMVs increased and elongated in 5 patients with shorter disease duration. The penetrating veins were well defined in 30 active lesions, whereas the veins were ill defined in 69 non-active lesions. Interestingly, well-defined penetrating veins were shown in 15 non-active lesions in the stable patients.

Conclusions

Enhanced T ₂ ^* -weighted MR angiography can detect cerebral vein characteristics in relapsing-remitting MS patients, which may provide important information on the pathogenesis of MS.

Key Points

? Enhanced T ₂ ^* -weighted magnetic resonance angiography (ESWAN) provides new insights into multiple sclerosis ? ESWAN venograms clearly demonstrate the internal cerebral and deep medullary veins ? The internal cerebral veins exhibit abnormalities in patients with relapsing-remitting MS ? Deep medullary veins exhibit different manifestations in patients with different disease duration     

Statisch-dynamische MR-Urographie Vergleich mit Ausscheidungsurographie und Szintigraphie bei experimentell induzierter Harntransportstörung (HTS)

Purpose. To assess the diagnostic value of combined static-dynamic MR urography (MRU) for the functional-morphological evaluation of experimentally induced urinary tract obstruction. Methods: Static-dynamic MRU – combination study with a respiratory-triggered 3D-IR-TSE sequence and a dynamic 2D-FFE sequence after Gd-DTPA and furosemide – was obtained in comparison with ^99mTc-MAG3 diuretic renal scintigraphy (DRS), excretory urography (EU) and ultrasound (US) in 29 healthy piglets and in 20 piglets with surgically induced ureteric stenosis (total of 50 postoperative examination blocks). Results: MRU allowed complete depiction of the urinary tract in all controls, in operated piglets the stenosis was always correctly identified. Quality of MRU was superior to EU in 36 of 43 comparative studies. Calculation of single kidney function from parenchymal renograms, and assessment of urinary excretion from whole-kidney renograms resulted in a highly significant agreement of MRU with DRS. Conclusion: Static-dynamic MR urography allows excellent depiction of experimentally induced urinary tract obstruction, and reliable assessment of individual renal function and urinary excretion. Two advantages of the method stand out, it does not require radiation and it permits a functional-morphological correlation.     

Facile synthesis of carbon-11-labeled arylpiperazinylthioalkyl derivatives as new PET radioligands for imaging of 5-HT1AR

Carbon-11-labeled arylpiperazinylthioalkyl derivatives, 2-((4-(4-(2-[¹¹C]methoxyphenyl)piperazin-1-yl)butyl)thio)benzo[d]oxazole ([¹¹C]5a), 2-((4-(4-(2-[¹¹C]methoxyphenyl)piperazin-1-yl)butyl)thio)-5,7-dimethylbenzo[d]oxazole ([¹¹C]5c), 2-((4-(4-(2-[¹¹C]methoxyphenyl)piperazin-1-yl)butyl)thio)benzo[d]thiazole ([¹¹C]5e), 2-((6-(4-(2-[¹¹C]methoxyphenyl)piperazin-1-yl)hexyl)thio)benzo[d]oxazole ([¹¹C]5g), 2-((6-(4-(2-[¹¹C]methoxyphenyl)piperazin-1-yl)hexyl)thio)-5,7-dimethylbenzo[d]oxazole ([¹¹C]5i), and 2-((6-(4-(2-[¹¹C]methoxyphenyl)piperazin-1-yl)hexyl)thio)benzo[d]thiazole ([¹¹C]5k), were prepared from their corresponding phenol precursors with [¹¹C]CH₃OTf through O-[¹¹C]methylation and isolated by a simplified solid-phase extraction (SPE) method using a Sep-Pak Plus C18 cartridge in 50-60% (n=5) radiochemical yields based on [¹¹C]CO₂ and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 277.5±92.5 GBq/μmol (n=5).