Automatic radiolabeling of the norepinephrine transporter targeted tracer 18F-mFBG and evaluation of 18F-mFBG PET/CT imaging in pheochromocytoma / 中华核医学与分子影像杂志

Objective:To fulfill the automatic radiolabeling of the norepinephrine transporter (NET) trancer 18F-meta-fluorobenzylguanidine (mFBG), and explore the 18F-mFBG PET/CT imaging effect of pheochromocytoma. Methods:On the basis of the chemical structure of mFBG, a spirocyclic iodonium ylide was used as the precursor to undergo a 3-step reaction sequence (radiofluorination, deprotection and neutralization) on AllinOne synthesis module. Purification by high performance liquid chromatography and formulation were conducted to generate 18F-mFBG. The corresponding quality control tests of 18F-mFBG product was performed. Afterwards, a postoperative patient with pheochromocytoma underwent 18F-mFBG PET/CT imaging. Results:The radiosynthesis was accomplished within 70 min, and 18F-mFBG was obtained in (17.8±2.4)% non-decay-corrected radiochemical yield ( n=5), with radiochemical purity >97% and molar activity >59.2 GBq/μmol. Sterility test, bacterial endotoxins test, abnormal toxicity test and the acetonitrile residue all met the requirements of Pharmacopoeia of the People′ s Republic of China (2020 Volume Ⅳ). The 18F-mFBG PET/CT imaging disclosed high uptake in pheochromocytoma and clear localization of lesions. Conclusions:The automatic radiolabeling of the NET targeted tracer 18F-mFBG is successfully realized by commercially available synthesis module, and the production quality meets all requirements for clinical translation. 18F-mFBG has a potential to image neuroendocrine lesions in clinical setting.

Tuning Peptide Structure and Function through Fluorobenzene Stapling.

Cyclic peptides are promising next-generation therapeutics with improved biological stability and activity. A catalyst-free stapling method for cysteine-containing peptides has been developed that enables fine-tuning of the macrocycle by using the appropriate regioisomers of fluorobenzene linkers. Stapling was performed on the unprotected linear peptide or, more conveniently, directly on-resin after peptide synthesis. NMR spectroscopy and circular dichroism studies demonstrate that the type of stapling can tune the secondary structures of the peptides. The method was applied to a set of potential agonists for melanocortin receptors, generating a library of macrocyclic potent ligands with ortho, meta or para relationships between the thioethers. Their small but significant differences in potency and efficacy demonstrate how the method allows facile fine-tuning of macrocyclic peptides towards biological targets from the same linear precursor.

Halogen and Chalcogen Bonding Between the Triphenylphosphine Chalcogenides (Ph3 P=E; E=O, S, Se) and Iodofluorobenzenes.

A series of cocrystals of Ph3 P=E (E=O, S, Se) with organoiodines were studied to understand the roles of noncovalent interactions including chalcogen (ChB) and halogen (XB) bonding in their formation. The structure of the cocrystal of Ph3 P=S and 1,2-diiodotetrafluorobezene was determined, which demonstrates a similar chalcogen⋅⋅⋅iodine XB pattern to the previously reported isomorphic Ph3 P=Se structure. The cocrystalline structures resulting from the combination of 1,3-diiodotetrafluorobenzene (1,3-F4 DIB), as well as iodopentafluorobenzene, with all three triphenylphosphine chalcogenides, were also determined. The (Ph3 P=Se) ⋅ (1,3-F4 DIB) cocrystal presents a rare example of a selenium⋅⋅⋅organoiodine ChB. The observed ChB and XB interactions have normalized distance parameters (RXB ) ranging from 0.80 to 0.98. The strength of the XB and ChB interactions were analyzed using natural bond orbital (NBO) theory, with calculated energies falling between 3.14 kcal/mol and 12.81 kcal/mol.

Fabrication and evaluation of a fluorophilic adsorbent for multiple monolithic fiber solid-phase microextraction of fluorobenzenes.

A new type of highly fluorinated monolith (HFM) was fabricated and used as adsorbent of multiple monolithic fiber solid-phase microextraction (MMF-SPME). To prepare the HFM, a fluorinated monomer, 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoroheptyl acrylate was in situ copolymerized with dual cross-linkers (divinylbenzene and ethylenedimethacrylate). The fabrication parameters including the content of monomer and porogenic solvent in the polymerization mixture were optimized to obtain expected extraction performance and life span. The physicochemical properties of the HFM were systematically investigated with elemental analysis, infrared spectroscopy, scanning electron microscopy and mercury intrusion porosimetry. The effective extraction of six fluorobenzenes was selected as a paradigm to demonstrate the fluorophilic characteristic of HFM/MMF-SPME. At the same time, a convenient and effective method for the determination of trace fluorobenzenes in environmental water samples was developed by coupling HFM/MMF-SPME with high performance liquid chromatography/diode array detection (HFM/MMF-SPME-HPLC/DAD). Results indicated that the limits of detection (S/N=3) for targeted compounds were in the range of 1.09-5.88µg/L. The intra-day and inter-day precision (relative standard deviations, n=4, %) at two spiked concentrations were 4.2-10.6% and 6.1-10.8%, respectively. Finally, the developed method was successfully applied to the analysis of fluorobenzenes in spiked real water samples with satisfactory recoveries and repeatability.

Effects of Rosuvastatin and Losartan on expression of caveolin-1 in cultured human monocyte-macrophage cells induced by oxidized low density lipoprotein / 中国医师杂志

Objective To investigate the effects,mechanisms,and the optimum doses of Rosuvastatin and Losartan on expression of caveolin-1 in cultured human monocyte-macrophage cells which were induced by oxidized low density lipoprotein(ox-LDL).Methods Human-monocyte cells were separated and changed into the human monocyte-macrophage cells.The model of amerosclerosis was set up.These cells were incubated in different doses of Rosuvastatin(0.1,1.0,5.0 μmol/L) and Losartan (10,50,100 μmol/L),and then cultured in combination of two drags (5.0 μmol/L + 100 μmol/L).Expression of caveolin-1 mRNA was determined with real-time fluorescent quantitative polymerase chain reaction (RT-PCR).Results In ox-LDL group,caveolin-1 mRNA was decreased sharply relative to control group [(0.2533 ±0.00973) vs (0.9410 ±0.03677)] in a concentration-dependent manner (P ＜0.01).Compared to ox-LDL group,expressions of Caveolin-1 mRNA were increased gradually in different doses of Rosuvastatin alone and Losartan alone group [(0.5198 ± 0.04840),(0.6183 ± 0.06740),(0.7257 ± 0.03052) vs (0.2533 ± 0.00973) ; (0.3350 ± 0.04177),(0.4428 ± 0.03804),(0.6049 ± 0.02627) vs (0.2533 ± 0.00973)] in a concentration-dependent manner (P ＜ 0.01) ; the summit expressions of caveolin-1 mRNA were emerged in using Rosuvastatin and Losartan together (F =59.119,P ＜ 0.01).Conclusions Rosuvastatin and Losartan may be responsible for the expression of caveolin-1 in human monocyte-macrophage cells that were induced by ox-LDL.The expressions were up-regulated with dose dependent manner of these drugs,and got the crest stage when using optimum doses of Rosuvastatin and Losartan together.

Effects and mechanism of different doses of rosuvastatin on expression of tissue factor in cultured human monocyte-macrophage cells induced by oxidized low density lipoprotein / 中国医师杂志

Objective To investigate the effects and mechanism of different doses of rosuvastatin on expression of tissue factor(TF) in cultured human monocyte-macrophage cells which were induced by oxidized low density lipoprotein (ox-LDL).Methods The human monocyte-macrophage cells were divided into seven groups:control group,ox-LDL group,poly-insine monophosphate group,different doses of rosuvastatin group(0.01 μmol/L,0.1 μmol/L,1 μmol/L,5 μmol/L).The expression of LOX-1 mRNA and TF mRNA was assayed by RT-PCR.The enzyme-linked immunosorbent assay was performed to determine the protein concentration of TF.Results Effects of different doses of rosuvastatin on expressions of LOX-1mRNA,TF mRNA and TF in cultured human monocyte-macrophage cells induced by ox-LDL:comparison among seven groups,the difference was statistically significant (F =91.334,58.833,103.552,P ＜0.05).Compared with control group,the expressions of LOX-1 mRNA,TF mRNA and TF were increased in the ox-LDL group[(3.25156 ± 0.15772) vs (1 ±0) ;(2.522451 ±0.138967) vs (1 ±0) ;(207.7233± 1.154701)ng/L vs (184.8467 ± 0.871799)ng/L],and they were in a concentration-dependent manner (P ＜ 0.05).Compared with the PolyⅠ group and the different doses of rosuvastatin group,the expressions of LOX-1 mRNA,TF mRNA and TF were in the ox-LDL group,and the different doses of rosuvastatin were decreased by dose-dependent manner.It was in a concentration dependent manner (P ＜ 0.05).Different doses of rosuvastatin were compared between groups (between each group P ＜ 0.05),the difference between each two groups was statistically significant (P ＜ 0.05).Conclusions LOX-1 may be responsible for the expression of TF in Human monocyte-macrophage cells induced by ox-LDL.Rosuvastatin by dose dependent manner and by means of ox-LDL reduced monocyte-macrophage LOX-1 mRNA and TF mRNA expressions,which reduced expression of TF.

Effect and mechanism of rosuvastatin on the expression of tissue factor in cultured human monocytemacrophages cell induced by oxidized low density lipoprotein / 中国医师杂志

ObjectiveTo investigate the effects and mechanism of rosuvastatin on the expression of tissue factor in cultured human monocyte-macrophages cells which was induced by oxidized low density lipoprotein(ox-LDL).MethodsThe human monocyte-macrophages cells were divided into four groups:control group,ox-LDL group,Poly-inosine monophosphate (Poly Ⅰ) group,rosuvastatin group.The expression of LOX-1mRNA and TF mRNA was assayed by RT-PCR.The ELISA was performed to determine the protein concentration of TF.ResultsCompared with control group,the expression of LOX-1 mRNA and TF mRNA was increased in the ox-LDL group[ (3.25156±0.15772) vs (1±0) ; (2.522451±0.138967) vs (1±0) ],and it was in a concentration-dependent manner (P＜0.01).Compared with the expression of LOX-1 mRNA in the Poly-inosine monophosphate group and rosuvastatin group,TF mRNA were decreased in the ox-LDL group[ (2.95139±0.157253) vs(3.25156±0.15772) ; (2.877343±0.156558) vs(3.25156±0.15772) ; (1.811956±0.169699) vs (2.522451±0.138967) ; (1.687701±0.174647) vs (2.522451±0.138967)],and it was in a concentration-dependent manner(P＜0.05).Compared with control group,the expression of TF in the ox-LDL group was increased [(207.7233±1.154701) vs (184.8467±0.871799) ],and it was in a concentration-dependent manner (P＜0.01).Compared with the Poly-inosine monophosphate group and rosuvastatin group [(197.8733±1.505003) vs (207.7233±1.154701) ;(202.9567±2.722744)vs(207.7233±1.154701) ],the expression of TF in the ox-LDL group were decreased,and it was in a concentration-dependent manner (P＜0.05).ConclusionsLOX-1 may be responsible for the expression of TF in human monocyte-macrophages cells induced by ox-LDL.Rosuvastatin is able to down-regulate the expression of LOX-1mRNA in human monocyte-macrophages cells through oxLDL,and TF mRNA and TF expression can be reduced.