The synthesis of radiolabelled 1-(2′-Fluoro-2′-deoxy-β-D-ribofuranosyl)-uracil and 1-(2′-chloro-2′-deoxy-β-D-ribofuranosyl)uracil

Radiolabelled derivatives of 1-(2′fluoro-2′-deoxy-β-D-ribofuranosyl)uracil 3 (2′-FUdR) and 1-(2′-chloro-2′-deoxy-β-D-ribofuranosyl)uracil 4 (2′-ClUdR) were synthesized for evaluation as diagnostic radiopharmaceuticals. 6-[³H]-2′-FUdR (21% radiochemical yield from 6-[³H]-uridine; 4.26 GBq mmol⁻¹) and 2-[¹⁴C]-2′-FUdR (25% radiochemical yield; 1.85 GBq mmol⁻¹ were prepared by reaction of anhydrous hydrogen fluoride (AHF) with 6-[³H]- or 2-[¹⁴C]-labelled 2,2′-anhydro-1-β-D-arabinofuranosyluracil 2 (2,2′-AUR). 6-[³H]-2′-ClUdR (53% radiochemical yield; 11.1 GBq mmol^-t-1) was prepared by reaction of CaCl₂ with 6-[³H]-2,2′-AUR. Reaction of [¹⁸F]-AHF with 2,2′-AUR afforded 2′-[¹⁸F]-2′-FUdR in low radiochemical yield while reaction of 2,2′-AUR with [³⁶Cl]-NaCl and trifluoroacetic acid gave 2′-[³⁶Cl]-2′-ClUdR (30% radiochemical yield; 5.46 MBq mmol⁻¹). 2′-[^34mCl]-2′-ClUdR was similarly prepared using [^34mCl]-MgCl₂ or [^34mCl]-Dowex 21-K resin in 2.7% (16.8 MBq mmol⁻¹) and 36% (0.304 GBq mmol⁻¹) radiochemical yield respectively.     

A facile and rapid automated synthesis of 3′-deoxy-3′-[18F]fluorothymidine

AimTo develop a simplified and fully automated synthesis procedure of 3′-deoxy-3′-[¹⁸F]fluorothymidine ([¹⁸F]FLT) using PET-MF-2V-IT-I synthesis module.MethodsSynthesis of [¹⁸F]FLT was performed using PET-MF-2V-IT-I synthesis module by one-pot two-step reaction procedure, including nucleophilic fluorination of 3-N-t-butoxycarbonyl-1-[5′-O-(4,4′-dimethoxy triphenylmethyl)-2′-deoxy-3′-O-(4-nitrobenzenesulfonyl)-β-d-threopentofuranosyl]thymine (15 mg) as the precursor molecule with [¹⁸F]fluoride, and subsequent hydrolysis of the protecting group with 1.0 M HCl at the same reaction vessel and purification with SEP PAK cartridges instead of the HPLC system.ResultsThe automated synthesis of [¹⁸F]FLT with SEP PAK purification gave corrected radiochemical yield of 23.2±2.6% (n=6, uncorrected yield: 16–22%) and radiochemical purity of >97% within the total synthesis time of 35 min.ConclusionThe fully one-pot automated synthesis procedure with SEP PAK purification can be applied to the fully automated synthesis of [¹⁸F]FLT using commercial [¹⁸F]FDG synthesis module.     

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.     

Comparison of 3′-deoxy-3′-[18F]fluorothymidine positron emission tomography (FLT PET) and FDG PET/CT for the detection and characterization of pancreatic tumours

Purpose

Despite recent advances in clinical imaging modalities, differentiation of pancreatic masses remains difficult. Here, we tested the diagnostic accuracy of molecular-based imaging including 3′-deoxy-3′-[¹⁸F]fluorothymidine (FLT) positron emission tomography (PET) and [¹⁸F]fluorodeoxyglucose (FDG) PET/CT in patients with suspected pancreatic masses scheduled to undergo surgery.

Methods

A total of 46 patients with pancreatic tumours suspicious for malignancy and scheduled for resective surgery were recruited prospectively. In 41 patients, FLT PET and FDG PET/CT scans were performed. A diagnostic CT performed on a routine basis was available in 31 patients. FLT PET and FDG PET/CT emission images were acquired according to standard protocols. Tracer uptake in the tumour [FDG and FLT standardized uptake value (SUV)] was quantified by the region of interest (ROI) technique. For FDG PET/CT analysis, correct ROI placement was ensured via side-by-side reading of corresponding CT images.

Results

Of 41 patients, 33 had malignancy, whereas 8 patients had benign disease. Visual analysis of FDG and FLT PET resulted in sensitivity values of 91% (30/33) and 70% (23/33), respectively. Corresponding specificities were 50% (4/8) for FDG PET and 75% (6/8) for FLT PET. In the subgroup of patients with contrast-enhanced CT (n?=?31), sensitivities were 96% (PET/CT), 88% (CT alone), 92% (FDG PET) and 72% (FLT PET), respectively. Mean FLT uptake in all malignant tumours was 3.0 (range SUV_max 1.1–6.5; mean FDG SUV_max 7.9, range 3.3–17.8; p?Conclusion For differentiation of pancreatic tumours, FDG PET and FDG PET/CT showed a higher sensitivity but lower specificity than FLT PET. Interestingly, visual analysis of FLT PET led to two false-positive findings by misinterpreting physiological bowel uptake as pathological FLT uptake in the pancreas. Due to the limited number of patients, the clinical value of adding FLT PET to the diagnostic workup of pancreatic tumours remains to be determined.     

3′-Deoxy-3′-[18F]fluorothymidine (FLT) uptake in breast cancer cells as a measure of proliferation after doxorubicin and docetaxel treatment

IntroductionThe nucleoside analogue [¹⁸F]fluorothymidine (FLT) has been designed as a marker of cell proliferation that can be imaged in vivo by positron emission tomography. Clinical pilot studies have demonstrated decreasing FLT uptake following antiproliferative chemotherapy of breast cancer. However, the significance of posttreatment FLT uptake has not been evaluated at the cell level. The aim of this study was to investigate whether FLT uptake detects proliferation inhibition induced by docetaxel or doxorubicin treatment in an in vitro breast cancer model.MethodsBreast cancer cells (MCF-7) were treated with docetaxel or doxorubicin for 24 h at drug doses inducing 25–99% inhibition of clonogenic survival (IC₂₅ to IC₉₉). Cellular FLT uptake was estimated at 4 h and at 1, 3 and 5 days interval from chemotherapy. [³H]Thymidine incorporation and S-phase fraction were measured for comparison. Analysis of variance and the Bland–Altman difference plot were employed for statistical analysis.ResultsAfter treatment, FLT uptake was declined in dependence of the proliferation inhibition mediated by both chemotherapeutic agents (all P<.0001). The decrease of FLT was greater after doxorubicin treatment than after the corresponding docetaxel dose. With doxorubicin (IC₉₉), FLT accumulation was reduced by 70% as early as 4 h after treatment. FLT uptake was closely correlated to [³H]thymidine incorporation and S-phase fraction (r=.84 to .93).ConclusionsRight after docetaxel or doxorubicin treatment, FLT uptake corresponds to the reduction of tumor cell proliferation induced. [¹⁸F]FLT appears promising for monitoring chemosensitivity in breast cancer.     

A useful EGFR-TK ligand for tumor diagnosis with SPECT: development of radioiodinated 6-(3-morpholinopropoxy)-7-ethoxy-4-(3′-iodophenoxy)quinazoline

Objective

Epidermal growth factor receptor tyrosine kinase (EGFR-TK) represents an attractive target for tumor diagnosis agents. Previously, radioiodinated 4-(3-iodophenoxy)-6,7-diethoxyquinazoline (PHY) was reported to possess good characteristics as a tumor imaging agent. We have explored the feasibility of developing tumor diagnosis ligands superior to radioiodinated PHY.

Methods

New phenoxyquinazoline derivatives were designed with various side chains introduced to the 6th position of PHY. The IC₅₀ values of the new derivatives to interrupt EGFR-TK phosphorylation were evaluated and compared to well-known EGFR-TK inhibitors. Tumor uptake studies of the new ¹²⁵I-labeled derivatives were conducted with A431 tumor-bearing mice. Selectivity and binding characteristics were analyzed by in vitro blocking studies and a binding assay. Furthermore, SPECT/CT scans were performed using A431 tumor-bearing mice.

Results

Six quinazoline derivatives were designed and synthesized, and among these, 6a–d were found to have relatively high EGFR-TK inhibitory potency. In tumor uptake studies, [¹²⁵I]6a ([¹²⁵I]PYK) was found to have the highest tumor uptake and longest retention in tumors. In contrast, [¹²⁵I]PYK was rapidly cleared from peripheral tissues, resulting in a high tumor-to-tissue ratio 24 h after injection. Moreover, the EGFR-TK selectivity of [¹²⁵I]PYK was confirmed by pretreatment experiments with specific EGFR-TK inhibitors. Furthermore, [¹²⁵I]PYK provided clear SPECT images of tumors.

Conclusions

Radioiodinated PYK, one of the newly synthesized quinazoline derivatives, was found to be a desirable ligand for EGFR-TK SPECT imaging. [¹²⁵I]PYK showed high tumor accumulation and selective EGFR-TK binding and also succeeded in delivering high contrast imaging of tumors. These favorable characteristics of [¹²⁵I]PYK suggest that the ¹²³I-labeled counterpart, [¹²³I]PYK, would have great potential for diagnostic SPECT tumor imaging.     

Evaluation of 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) kinetics correlated with thymidine kinase-1 expression and cell proliferation in newly diagnosed gliomas

Purpose

The thymidine analog 3′-deoxy-3′-[¹⁸F]fluorothymidine (¹⁸F-FLT) has been developed as a positron emission tomography (PET) tracer to assess the proliferation activity of tumors in vivo. The present study investigated the relationship between the kinetic parameters of ¹⁸F-FLT in vivo and thymidine kinase-1 (TK-1) expression and cell proliferation rate in vitro, and blood–brain barrier (BBB) breakdown in human brain gliomas.

Methods

A total of 21 patients with newly diagnosed gliomas were examined by ¹⁸F-FLT PET kinetic analysis. Maximum standardized uptake value (SUVmax) and tumor-to-normal (T/N) ratio of ¹⁸F-FLT in the tumor and ¹⁸F-FLT kinetic parameters in the corresponding contralateral region were determined. The expression levels of TK-1 protein and mRNA were determined by immunohistochemistry (IHC) and real-time polymerase chain reaction (PCR), respectively, using surgical specimens. The cell proliferation rate of the tumor was determined in terms of the Ki-67 labeling index. BBB breakdown was evaluated on MR images with contrast enhancement.

Results

¹⁸F-FLT SUVmax and T/N ratio were significantly correlated with the influx rate constant (K ₁; P?=?0.001 and P?<?0.001, respectively), but not with the phosphorylation rate constant (k ₃). IHC and real-time PCR studies demonstrated a significant correlation between K ₁ and TK-1 mRNA expression (P?=?0.001), but not between k ₃ and TK-1 protein and mRNA expression. Linear regression analysis revealed a significant correlation between K ₁ and the Ki-67 index (P?=?0.003), but not between k ₃ and the Ki-67 index. TK-1 mRNA expression was significantly correlated with the Ki-67 index (P?=?0.009). ¹⁸F-FLT SUVmax and T/N ratio were significantly correlated with BBB breakdown evaluated by contrast enhancement in MR images (P?=?0.003 and P?=?0.011, respectively).

Conclusion

These results indicate that ¹⁸F-FLT uptake in the tumor is significantly related to transport through the disrupted BBB, but not through phosphorylation activity. Although the tissue TK-1 expression reflects tumor proliferation activity, the phosphorylation rate constant k ₃ determined by ¹⁸F-FLT PET kinetic analysis does not accurately reflect TK-1 expression in the tissue and should not be used as a surrogate biomarker of cell proliferation activity in human brain gliomas.     

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.     

Investigation of the pharmacokinetics of 3′-deoxy-3′-[18F]fluorothymidine uptake in the bone marrow before and early after initiation of chemoradiation therapy in head and neck cancer

IntroductionThe kinetics of the bone marrow uptake of 3′-deoxy-3′-[¹⁸F]fluorothymidine (FLT) before and early after initiation of chemoradiation therapy was investigated in patients with head and neck cancer.MethodsFourteen subjects with head and neck cancer underwent FLT positron emission tomography (PET) at baseline and after 10 Gy of radiation therapy. Thirteen subjects also received one cycle of platinum-based chemotherapy before the second FLT PET. Kinetic parameters, including the flux constant based on compartmental analysis (K_FLT) and the Patlak constant (K_Patlak) for cervical marrow, were calculated. Standardized uptake values (SUVs) for the cervical marrow (inside the radiation field) and lumbar spine marrow (outside the radiation field) were also determined.ResultsThere was a significant drop in FLT uptake in the bone marrow inside the radiation field. Mean pretreatment uptake values for the cervical spine were SUV=3.08±0.66, K_FLT=0.045±0.016 min^?1 and K_Patlak=0.039±0.013 min^?1. After treatment, these values were SUV=0.74±0.19, K_FLT=0.011±0.005 min^?1 and K_Patlak=0.005±0.002 min^?1. Compartmental analysis revealed a significant drop in k₃ in irradiated cervical marrow. FLT uptake in the bone marrow outside the radiation field exhibited a significantly smaller decrease.ConclusionsThere is a marked decrease in FLT uptake in irradiated bone marrow after 10 Gy of radiation therapy to the head and neck. The drop in FLT uptake in irradiated marrow is due to a significant decrease in the net phosphorylation rate of FLT.     

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.     

[18F]3′-deoxy-3′-fluorothymidine PET for the diagnosis and grading of brain tumors

Abstract The aim of this study was to evaluate the feasibility of using [¹⁸F] 3-deoxy-3-fluorothymidine (FLT) positron emission tomography (PET) for the diagnosis and grading of brain tumors.Methods The patient population comprised 26 patients (15 males, 11 females) with brain tumors (n=18) or nontumorous lesions (n=8). 2-[¹⁸F]fluoro-2-deoxy-d-glucose (FDG) and FLT PET images were obtained using a dedicated PET scanner 1 h after the injection of 370 MBq of FDG or FLT. Uptake of FDG and FLT by the lesions was visually and semiquantitatively assessed in comparison with normal brain tissue.Results Of 26 brain lesions, four showed increased FDG uptake compared with normal gray matter (grade 5). These four lesions showed intensely increased FLT uptake and were all high-grade tumors. Twenty-two lesions with similar (grade 4) or decreased (grades 1–3) FDG uptake compared with normal gray matter showed variable pathology. Among the 18 brain tumors, FLT PET showed increased uptake in all 12 high-grade tumors but FDG uptake was variable. In 22 brain lesions with similar or decreased uptake compared with normal gray matter on FDG PET, the sensitivity and specificity of FLT PET for the diagnosis of brain tumor were 79% (11/14) and 63% (5/8), respectively. The uptake ratios of 14 brain tumors on FLT PET were significantly higher than the lesion to gray matter ratios (p=0.012) and lesion to white matter ratios (p=0.036) of FDG uptake and differed significantly between high (5.1±2.6) and low (2.1±1.1) grade tumors (p=0.029). In nine gliomas, FLT uptake was significantly correlated with the Ki-67 proliferation index (rho=0.817, p=0.007).Conclusion These findings indicate that FLT PET is useful for evaluating tumor grade and cellular proliferation in brain tumors. It displayed high sensitivity and good contrast in evaluating brain lesions that showed similar or decreased uptake compared with normal gray matter on FDG PET. FLT PET, however, did not appear to be sufficiently useful for differentiating tumors from nontumorous lesions.     

3′-Deoxy-3′-[18F]fluorothymidine and O-(2-[18F]fluoroethyl)-L-tyrosine PET in Patients with Suspicious Recurrence of Glioma after Multimodal Treatment: Initial Results of a Retrospective Comparative Study

Purpose

The purpose of this study was to compare the uptakes and diagnostic accuracies between 3′-deoxy-3′-[¹⁸F]fluorothymidine (FLT) and O-(2-[¹⁸F]fluoroethyl)-L-tyrosine (FET) PET in patients with a clinical suspicion of having a recurrence of glioma after multimodality treatment.

Methods

Thirty-two patients who underwent FLT and FET PET due to abnormal enhancement on magnetic resonance (MR) images were included. According to surgical confirmation or follow-up results, patients were divided into those with therapy-related benign changes (TRBCs) and those with recurrence. Recurrences were divided again into initial low-grade glioma (LGG) and high-grade glioma (HGG). The uptakes of FLT and FET were compared with the maximum standardized uptake value (SUVmax) and lesion-to-normal ratio (LNR). The diagnostic accuracies were compared via a receiver-operating-characteristic (ROC) curve analysis.

Results

The LNRs of FLT in recurrences with initial HGG (8.26 ± 5.02) were significantly higher than those in recurrences with initial LGG (3.43 ± 2.14) and TRBC (1.81 ± 0.60). The LNRs of FET in recurrence with initial HGG (2.70 ± 0.48) and LGG (3.03 ± 1.32) were significantly higher than those in the TRBC (1.60 ± 0.47). The areas under the ROC curve (AUCs) of FLT and FET for initial LGG were 0.768 and 0.893, respectively. The AUCs of FLT and FET for initial HGG were 1.000 and 0.964. However, there were no statistical significances. The results for comparing with SUVmax were the same as those with LNR.

Conclusions

Uptakes of FLT were different according to initial grade in patients with recurrent glioma, but those of FET were not. However, there were no statistical significances in the diagnostic accuracies according to initial grade between the two tracers in this study.     

肿瘤增殖显像剂3′-脱氧-3′-18F-氟代胸苷

18F-氟代脱氧葡萄糖（18F-FDG）是广泛用于肿瘤诊断的PET显像剂,由于所有细胞都利用葡萄糖,因此,18F-FDG不是特异的肿瘤显像剂.3′-脱氧-3′-18F-氟代胸苷（18F-FLT）克服了18F-FDG的局限性,并可以进行细胞增殖显像.对于肿瘤的PET研究,18F-FLT是理想的反映增殖特性的示踪剂,18F-FLT利用胸苷激酶催化的磷酸化作用来评价DNA复制过程,可以准确地评估肿瘤细胞DNA的合成和细胞增殖活性,可用于肿瘤的早期诊断及鉴别诊断、化疗和放疗的疗效监测,是很有希望和发展前途的PET显像剂.     

Rapid reductive-carboxylation of secondary amines,one pot synthesis of N′-(4-11C-methyl)imipramine

A new rapid high yield synthesis of radiolabeled N′-(4-¹¹C-methyl)imipramine has been developed using a reductive-carboxylation approach, in which ¹¹CO₂ is reacted with either N′-trimethylsilyldesimipramine or N′-lithium derivative of desimipramine, followed by lithium aluminum hydride reduction, to give no carrier added or carrier added¹¹C-labeled imipramine respectively. The final product is characterized by chromatographic and spectroscopic methods.     

Prognostic value of 3′-Deoxy-3′-18F-Fluorothymidine ([18F] FLT PET) in patients with recurrent malignant gliomas

Introduction3′-deoxy-3′-18F-fluorothymidine ([¹⁸F] FLT) PET has been proven to be of value in diagnosis and assessment of glioma grading, in differentiating tumor recurrence from necrosis, in response assessment and in predicting overall survival (OS) in the primary high grade glioma. In this study, we evaluated the value of [¹⁸F] FLT PET-CT in predicting the OS of patients with recurrent malignant glioma.MethodsFifty-six patients with recurrent malignant glioma were enrolled in this prospective study. The PET-CT and contrast-enhanced MRI scans were performed in all patients. Tumor volume was determined from both PET image (proliferative volume, PV) and MRI image (Vol-MRI). Patients were followed up clinically until death. The likelihood of using PET-derived parameters of SUV_max, tumor-to-normal (T/N) ratio, and PV to predict the OS of patients were assessed in comparison with Vol-MRI and other clinical parameters.ResultThe follow up periods for all patients ranged from 1.5 to 35.6 months with median of 9.8 months. Univariate analysis showed that the following parameters were significantly correlated with OS: grade of primary tumor (p = 0.042), Karnofsky performance score (KPS) (p = 0.041), T/N ratio (p < 0.01), Vol-MRI (p = 0.041), and PV (p < 0.001). However, multivariate Cox regression showed that only the PV (p < 0.001) and T/N ratio (p = 0.001) were independent predictors. The thresholds to predict OS were 16.88 cm³ for PV and 10.94 for T/N ratio. Kaplan–Meier analyses using these thresholds showed a significant discrimination between short and long OS groups (p < 0.001).ConclusionThe PV and T/N ratio of tumor on [¹⁸F] FLT PET-CT are independent predictors of survival in patients with recurrent malignant glioma. The PV on [¹⁸F] FLT PET seems to be more predictive than tumor volume on T1-weighted MRI for OS.     

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.     

PET measurement of D2 and S2 receptor binding of 3-N-([2′-18F]fluoroethyl)spiperone in baboon brain

The regional pharmacokinetic behavior in baboon brain of ¹⁸F-fluoroethyl-and ¹⁸F-fluoropropylspiperone (¹⁸FESP, ¹⁸FPSP) at specific activities1000 Ci/mmol was studied with PET. Four hours after injection of 5–10 mCi ¹⁸FESP, uptake in striatum was 0.048%±0.005% of injected dose per cm³, which is almost the same as with ¹⁸F-and ¹¹C-methylspiperone. While ¹⁸FPSP was taken up in much smaller amounts than ¹⁸FESP, striatum to cerebellum activity ratios were quite similar for both ligands (about 9 to 10 at 4 h p.i.). Because of its higher striatal uptake, ¹⁸FESP seems to be better suited for PET. Furthermore, relative binding to S₂ receptors was much smaller for FESP: competing cold S₂ antagonists (ritanserin, ketanserin) did not alter ¹⁸FESP binding to striatum, concurrently reducing uptake in frontal cortex by only 15%–20%. With coninjection of increasing amounts of cold FESP, saturation of ¹⁸FESP binding to striatum occurred at doses exceeding 10 g per kg. Quantitative analysis of radiolabelled ligand in arterial plasma (decrease to 8% at 4 h p.i.) demonstrated identical metabolic turnover for both ligands. Direct use of binding fractions from the saturation curve resulted in overestimation of the receptor density in striatum. Using the ¹⁸FESP plasma concentration time curve and the dynamic uptake data, k ₃ of a three compartment model could be determined by non linear regression. However, dramatic changes of the dependence of k ₃ on the specifically bound ligand concentration were observed even at small loading doses of FESP. Estimation of B _max yielded a D₂ receptor density of only 6 pmol per cm³ in baboon striatum.     

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.