Fully Automated Radiosynthesis of [F]mG4P027 for mGluR4 Imaging.

Fluorine-18 labeled N-(4-chloro-3-(((fluoro-F)methyl-d)thio)phenyl)picolinamide, [F] is a potent positron emission tomography (PET) radiotracer for metabotropic glutamate receptor 4 (mGluR4). Our previous in vitro and in vivo evaluations have demonstrated that this tracer is promising for further translational studies. To automate the radiosynthesis of [F], significant modifications were made to the manual process by carefully examining this process and addressing the root causes of the challenges associated with its automation.

Detailed radiosynthesis of [ F]mG4P027 as a positron emission tomography radiotracer for mGluR4.

We report here the detailed radiosynthesis of [ F]mG4P027, a metabotropic glutamate receptor 4 (mGluR4) PET radiotracer, which showed superior properties to the currently reported mGluR4 radiotracers. The radiosynthesis in the automated system has been challenging, therefore we disclose here the major limiting factors for the synthesis via step-by-step examination. And we hope this thorough study will help its automation for human use in the future.

Organomediated cleavage of benzoyl group enables an efficient synthesis of 1-(6-nitropyridin-2-yl)thiourea and its application for developing F-labeled PET tracers.

A novel organomediated cleavage of benzoyl group using ethane-1,2-diamine and acetic acid under neutral condition enables an efficient synthesis of 1-(6-nitropyridin-2-yl)thiourea, which previously has been challenging to prepare by conventional methods. The successful synthesis of 1-(6-nitropyridin-2-yl)thiourea as a synthon permits development of a variety of F labeled heterocycles as PET imaging ligands such as N-(pyridin-2-yl)thiazol-2-amine derivatives. The utility of this synthon is demonstrated with the synthesis of a F-labeled PET tracer for studying prion disease.

Synthesis and Characterization of [F]JNJ-46356479 as the First F-Labeled PET Imaging Ligand for Metabotropic Glutamate Receptor 2.

Purpose: Metabotropic glutamate receptor 2 (mGluR2) has been implicated in various psychiatric and neurological disorders, such as schizophrenia and Alzheimer's disease. We have previously developed [C]7 as a PET radioligand for imaging mGluR2. Herein, [F]JNJ-46356479 ([F]8) was synthesized and characterized as the first F-labeled mGluR2 imaging ligand to enhance diagnostic approaches for mGluR2-related disorders.

Design, Synthesis, and Characterization of Benzimidazole Derivatives as Positron Emission Tomography Imaging Ligands for Metabotropic Glutamate Receptor 2.

Three benzimidazole derivatives (-) have been synthetized as potential positron emission tomography (PET) imaging ligands for mGluR2 in the brain. Of these compounds, exhibits potent binding affinity (IC = 7.6 ± 0.

Current Progress and Perspective: Clinical Imaging of Islet Transplantation.

Islet transplantation has great potential as a cure for type 1 diabetes. At present; the lack of a clinically validated non-invasive imaging method to track islet grafts limits the success of this treatment. Some major clinical imaging modalities and various molecular probes, which have been studied for non-invasive monitoring of transplanted islets, could potentially fulfill the goal of understanding pathophysiology of the functional status and viability of the islet grafts.

Improved Synthesis of the Thiophenol Precursor -(4-Chloro-3-mercaptophenyl)picolinamide for Making the mGluR4 PET Ligand.

Recently [C]mG4P012 (previously [C]KALB012 and presently named as [C]PXT012253 by Prexton Therapeutics) had been used as a biomarker during the preclinical development of a potential therapeutic drug, PXT0002331 (an mGluR4 PAM), for PD and L-dopa-induced dyskinesia. [C]mG4P012 was shown to be a promising PET radioligand for mGluR4 in the monkey brain and for further development in human subjects. However, the previously reported multi-step synthesis of the thiophenol precursor suffered from low yields and difficult workup procedures.

Synthesis and Characterization of Fluorine-18-Labeled -(4-Chloro-3-((fluoromethyl-)thio)phenyl)picolinamide for Imaging of mGluR4 in Brain.

We have synthesized and characterized [F]--(4-chloro-3-((fluoromethyl-)thio)phenyl)-picolinamide ([F]) as a potential ligand for the positron emission tomography (PET) imaging of mGluR4 in the brain. Radioligand [F] displays central nervous system drug-like properties, including mGluR4 affinity, potent mGluR4 PAM activity, and selectivity against other mGluRs, as well as sufficient metabolic stability. Radiosynthesis was carried out in two steps.

Efficient synthesis of NIR emitting bis[2-(2'-hydroxylphenyl)benzoxazole] derivative and its potential for imaging applications.

Unassymetric bis[2-(2'-hydroxyphenylbenzoxole)] bis(HBO) derivatives with a DPA functionality for zinc binding have been developed with an efficient synthetic route, using the retrosynthetic analysis. Comparison of bis(HBO) derivatives with different substitution patterns allows us to verify and optimize their unique fluorescence properties. Upon binding zinc cation, bis(HBO) derivatives give a large fluorescence turn-on in both visible (λ ≈ 536 nm) and near-infrared (NIR) window (λ ≈ 746 nm).

[Effects of RAGE on Cell Proliferation and Tumor Growth in Pancreatic Cancer].

Objectives: To investigate the effect of receptor for advanced glycation end products (RAGE) on cell proliferation and tumor growth in nude mice with pancreatic cancer.

Methods: PANC-1 cells were transfected with shRNA -1, -2, -3 to down-regulate the expression of RAGE. Cholecystokinin octopeptide-8 (CCK-8), real-time PCR and Western blot were performed to test the impact of shRNA on the expressions of mRNAs and proteins of RAGE, matrix metalloproteinase-2 (MMP-2), MMP-9, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and vascular endothelial growth factor (VEGF).

Transjugular intrahepatic portosystemic shunt versus open splenectomy and esophagogastric devascularization for portal hypertension with recurrent variceal bleeding.

Background: Transjugular intrahepatic portosystemic shunt (TIPS) and open splenectomy and esophagogastric devascularization (OSED) are widely used to treat patients with portal hypertension and recurrent variceal bleeding (PHRVB). This study aimed to compare the effectiveness between TIPS and OSED for the treatment of PHRVB.

Methods: The data were retrospectively retrieved from 479 cirrhotic patients (Child-Pugh A or B class) with PHRVB, who had undergone TIPS (TIPS group) or OSED (OSED group) between January 1, 2010 and October 31, 2014.

Early complications after interventions in patients with acute pancreatitis.

Aim: To identify the possible predictors of early complications after the initial intervention in acute necrotizing pancreatitis.

Methods: We collected the medical records of 334 patients with acute necrotizing pancreatitis who received initial intervention in our center. Complications associated with predictors were analyzed.

Laparoscopic Splenectomy for the Elderly Liver Cirrhotic Patients With Hypersplenism: A Retrospective Comparable Study.

A growing body of evidence has supported the benefits of laparoscopic splenectomy (LS) for hypersplenism due to liver cirrhosis. With the increased proportion of elderly persons worldwide, it is necessary to investigate the risks and benefits of LS in elderly liver cirrhotic patients.From September 2003 to March 2012, LS and open splenectomy (OS) were performed for 21 (Group 1) and 19 (Group 3) patients, respectively, all of whom were 65 years of age and older; in addition, 39 patients who were <65 years old were treated with LS and referred to as Group 2.

Learning Curve for Laparoscopic Pancreaticoduodenectomy: a CUSUM Analysis.

Background: Laparoscopic pancreaticoduodenectomy (LPD), an advanced minimally invasive technique, has demonstrated advantages to open pancreaticoduodenectomy (OPD). However, this complex procedure requires a relatively long training period to ensure technical proficiency. This study was therefore designed to analyze the learning curve for LPD.

Regulating the expression of CD80/CD86 on dendritic cells to induce immune tolerance after xeno-islet transplantation.

Background: Antigen present cells (APCs) have been demonstrated to play dual roles in immune tolerance. Recently, compelling evidence indicates that APCs that express CD80, but not CD86 can protect allograft. We investigated whether modulation of CD80 in dendritic cells (DCs) offer protection for xeno-islets.

Clinical outcomes of combined necrotizing pancreatitis versus extrapancreatic necrosis alone.

Introduction: Extrapancreatic necrosis (EPN) alone, i.e., in the absence of pancreatic parenchyma necrosis has gradually come to be regarded as a separate entity of acute necrotizing pancreatitis (ANP).

Synthesis and evaluation of N-(methylthiophenyl)picolinamide derivatives as PET radioligands for metabotropic glutamate receptor subtype 4.

In recent years, mGlu4 has received great research attention because of the potential benefits of mGlu4 activation in treating numerous brain disorders, such as Parkinson's disease (PD). A specific mGlu4 PET radioligand could be an important tool in understanding the role of mGlu4 in both healthy and disease conditions, and also for the development of new drugs. In this study, we synthesized four new N-(methylthiophenyl)picolinamide derivatives 11-14.

Functional modulation of G-protein coupled receptors during Parkinson disease-like neurodegeneration.

G-protein coupled dopamine and metabotropic glutamate receptors (mGlu) can modulate neurotransmission during Parkinson's disease (PD)-like neurodegeneration. PET imaging studies in a unilateral dopamine denervation model (6-OHDA) showed a significant inverse correlation of presynaptic mGlu4 and postsynaptic mGlu5 expression in the striatum and rapidly declining mGlu4 and enhanced mGlu5 expression in the hippocampus during progressive degeneration over time. Immunohistochemical studies verified the decreased mGlu4 expression in the hippocampus on the lesion side but did not show difference in mGlu5 expression between lesion and control side.

[Effect of CD86 Gene Modified Recipient Dendritic Cell on Mix Cultured Donor-derived Islet with Recipient-derived Lymphocyte in vitro].

Objective: To investigate the effect of CD86 gene modified recipient dendritic cell (DC) on mix cultured donor-derived islet with recipient-derived lymphocyte in vitro.

Methods: DCs were separated from bone marrow of BALB/c mice and identified by flow cytometry. Chemically synthesized CD86 siRNA was transferred into DC.

Re-exploring the N-phenylpicolinamide derivatives to develop mGlu4 ligands with improved affinity and in vitro microsomal stability.

In recent years, mGlu4 has received great attention and research effort because of the potential benefits of mGlu4 activation in treating numerous brain disorders, such as Parkinson's disease (PD). Many positive allosteric modulators of mGlu4 have been developed. To better understand the role of mGlu4 in healthy and disease conditions, we are interested in developing an mGlu4 selective radioligand for in vivo studies.

Co-operative binding assay for the characterization of mGlu4 allosteric modulators.

The interest in the role of metabotropic glutamate receptor 4 (mGlu4) in CNS related disorders has increased the need for methods to investigate the binding of allosteric drug candidates. Our aim is to present the first fully characterized in vitro binding assay of mGlu4 positive allosteric modulators (PAMs). Results suggest that mGlu4 PAMs have characteristic co-operative binding with orthosteric glutamate, which offers a notable insight to the further development of mGlu4 targeted therapies.

Laparoscopic pancreaticoduodenectomy: single-surgeon experience.

Background: Innovations in surgical strategies and technologies have facilitated laparoscopic pancreaticoduodenectomy (LPD). However, data regarding the short-term and long-term results of LPD are sparse, and this procedure is the primary focus of the current study.

Methods: Between October 2010 and October 2013, a total of 31 consecutive patients received LPD, including hand-assisted laparoscopic pancreaticoduodenectomy, total laparoscopic pancreaticoduodenectomy, and laparoscopic pylorus-preserving pancreaticoduodenectomy.

Radiosynthesis and evaluation of an 18F-labeled positron emission tomography (PET) radioligand for metabotropic glutamate receptor subtype 4 (mGlu4).

Four 4-phthalimide derivatives of N-(3-chlorophenyl)-2-picolinamide were synthesized as potential ligands for the PET imaging of mGlu4 in the brain. Of these compounds, N-(3-chloro-4-(4-fluoro-1,3-dioxoisoindolin-2-yl)phenyl)-2-picolinamide (3, KALB001) exhibited improved binding affinity (IC50 = 5.1 nM) compared with ML128 (1) and was subsequently labeled with (18)F.

Timing of intervention in necrotizing pancreatitis.

Background: The best available evidence suggests that surgical intervention should be delayed where possible until four weeks after the onset of pancreatitis. Subgroups that may benefit from early or delayed intervention have not been identified.

Methods: This study reviewed a prospective database with 223 patients of necrotizing pancreatitis who received intervention.

Development of [(123)I]IPEB and [(123)I]IMPEB as SPECT Radioligands for Metabotropic Glutamate Receptor Subtype 5.

mGlu5 play an important role in physiology and pathology to various central nervous system (CNS) diseases. Several positron emission tomography (PET) radiotracers have been developed to explore the role of mGlu5 in brain disorders. However, there are no single photon emission computed tomography (SPECT) radioligands for mGlu5.