[F]MAGL-4-11 positron emission tomography molecular imaging of monoacylglycerol lipase changes in preclinical liver fibrosis models.

Monoacylglycerol lipase (MAGL) is a pivotal enzyme in the endocannabinoid system, which metabolizes 2-arachidonoylglycerol (2-AG) into the proinflammatory eicosanoid precursor arachidonic acid (AA). MAGL and other endogenous cannabinoid (EC) degrading enzymes are involved in the fibrogenic signaling pathways that induce hepatic stellate cell (HSC) activation and ECM accumulation during chronic liver disease. Our group recently developed an F-labeled MAGL inhibitor ([F]MAGL-4-11) for PET imaging and demonstrated highly specific binding and .

Large-Volume Intrathecal Administrations: Impact on CSF Pressure and Safety Implications.

The increasing number of studies demonstrates the high potency of the intrathecal (IT) route for the delivery of biopharmaceuticals to the central nervous system (CNS). Our earlier data exhibited that both the infused volume and the infusion rate can regulate the initial disposition of the administered solute within the cerebrospinal fluid (CSF). This disposition is one of key factors in defining the subsequent transport of the solute to its intended target.

Design, Synthesis, and Evaluation of F-Labeled Monoacylglycerol Lipase Inhibitors as Novel Positron Emission Tomography Probes.

Dysfunction of monoacylglycerol lipase (MAGL) is associated with several psychopathological disorders, including drug addiction and neurodegenerative diseases. Herein we design, synthesize, and evaluate several irreversible fluorine-containing MAGL inhibitors for positron emission tomography (PET) ligand development. Compound (identified from a therapeutic agent) was advanced for F-labeling via a novel spirocyclic iodonium ylide (SCIDY) strategy, which demonstrated high brain permeability and excellent specific binding.

The Configuration of the Perivascular System Transporting Macromolecules in the CNS.

Large blood vessels entering the CNS are surrounded by perivascular spaces that communicate with the cerebrospinal fluid and, at their termini, with the interstitial space. Solutes and particles can translocate along these perivascular conduits, reportedly in both directions. Recently, this prompted a renewed interest in the intrathecal therapy delivery route for CNS-targeted therapeutics.

Synthesis and Preliminary Evaluations of a Triazole-Cored Antagonist as a PET Imaging Probe ([F]N2B-0518) for GluN2B Subunit in the Brain.

GluN2B is the most studied subunit of N-methyl-d-aspartate receptors (NMDARs) and implicated in the pathologies of various central nervous system disorders and neurodegenerative diseases. As pan NMDAR antagonists often produce debilitating side effects, new approaches in drug discovery have shifted to subtype-selective NMDAR modulators, especially GluN2B-selective antagonists. While positron emission tomography (PET) studies of GluN2B-selective NMDARs in the living brain would enable target engagement in drug development and improve our understanding in the NMDAR signaling pathways between normal and disease conditions, a suitable PET ligand is yet to be identified.

Practical Radiosynthesis and Preclinical Neuroimaging of [11C]isradipine, a Calcium Channel Antagonist.

In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4-(benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine -3-carboxylic acid) was reacted with [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF in an HPLC injector loop to produce the radiotracer in a good yield (6 ± 3% uncorrected radiochemical yield) and high specific activity (143 ± 90 GBq·µmol-1 at end-of-synthesis). PET imaging of normal rats revealed rapid brain uptake at baseline (0.

Skin rejuvenation with non-invasive pulsed electric fields.

Degenerative skin diseases affect one third of individuals over the age of sixty. Current therapies use various physical and chemical methods to rejuvenate skin; but since the therapies affect many tissue components including cells and extracellular matrix, they may also induce significant side effects, such as scarring. Here we report on a new, non-invasive, non-thermal technique to rejuvenate skin with pulsed electric fields.

Physiology of the intrathecal bolus: the leptomeningeal route for macromolecule and particle delivery to CNS.

Presently, there are no effective treatments for several diseases involving the CNS, which is protected by the blood-brain, blood-CSF, and blood-arachnoid barriers. Traversing any of these barriers is difficult, especially for macromolecular drugs and particulates. However, there is significant experimental evidence that large molecules can be delivered to the CNS through the cerebrospinal fluid (CSF).

Radioiodination of aryl-alkyl cyclic sulfates.

Among the currently available positron emitters suitable for Positron Emission Tomography (PET), (124)I has the longest physical half-life (4.2 days). The long half-life and well-investigated behavior of iodine in vivo makes (124)I very attractive for pharmacological studies.

Investigation of intrathecal transport of NPT002, a prospective therapeutic based on phage M13, in nonhuman primates.

Presently, there are no effective treatments for conditions characterized by protein misfolding, such as Alzheimer's, Parkinson's, and other diseases involving CNS. Since misfolding occurs at the earliest stage of the disease, it is likely to be involved in subsequent pathological developments. It has been found that NPT002 (bacteriophage M13) directly dissociates aggregates of misfolded proteins that form amyloid, including amyloid-β, tau and α-synuclein.

Delivery of proteins to CNS as seen and measured by positron emission tomography.

Presently, there are no effective treatments for several diseases involving the central nervous system (CNS). While several novel molecular approaches are being developed, many of them require delivery of macromolecular or supramolecular agents to the CNS tissues protected by the blood-brain and blood-arachnoid barriers. A variety of approaches that are being developed for overcoming or bypassing the barriers are based on complex transfer processes.

CNS penetration of intrathecal-lumbar idursulfase in the monkey, dog and mouse: implications for neurological outcomes of lysosomal storage disorder.

A major challenge for the treatment of many central nervous system (CNS) disorders is the lack of convenient and effective methods for delivering biological agents to the brain. Mucopolysaccharidosis II (Hunter syndrome) is a rare inherited lysosomal storage disorder resulting from a deficiency of iduronate-2-sulfatase (I2S). I2S is a large, highly glycosylated enzyme.

Iodine-124 as a label for pharmacological PET imaging.

With the growing number of biotechnology products and drug delivery systems entering preclinical and clinical studies, pharmacological imaging studies with PET play an increasingly significant role. Such studies often require investigation of slow and complex pharmacokinetics (PK). This suggests labeling of the drug candidate with radionuclides that have long physical half-lives.

Involvement of skeletal muscle gene regulatory network in susceptibility to wound infection following trauma.

Despite recent advances in our understanding the pathophysiology of trauma, the basis of the predisposition of trauma patients to infection remains unclear. A Drosophila melanogaster/Pseudomonas aeruginosa injury and infection model was used to identify host genetic components that contribute to the hyper-susceptibility to infection that follows severe trauma. We show that P.

Semisynthetic hydrophilic polyals.

Non-bioadhesive, fully biodegradable soluble polymers would be very instrumental in advanced biomedical applications, such as gene and drug delivery and tissue engineering. However, rational development of such materials is hindered by the complexity of macromolecule interactions with biological milieu. The prevalence of carbohydrates in naturally occurring interface structures suggests an alternative, biomimetic approach.

Fully degradable hydrophilic polyals for protein modification.

Modification of proteins with hydrophilic polymers is an effective strategy for regulation of protein pharmacokinetics. However, conjugates of slowly or non-biodegradable materials, such as poly(ethylene glycol), are known to cause long-lasting cell vacuolization, in particular in renal epithelium. Conjugates of more degradable polymers, e.

Synthesis of a macromolecular camptothecin conjugate with dual phase drug release.

A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.

A systemic route for drug loading to lymphatic phagocytes.

Lymph nodes are primary germination and proliferation sites for many types of pathogens. Maintaining therapeutic levels of appropriate chemotherapeutic agents in the lymph node tissue is critical for the treatment of both infection and cancer. This study was intended to develop a systemic route for loading lymph node phagocytes with drugs, using a lymph node specific nanocarrier.

Theoretical considerations of RES-avoiding liposomes: Molecular mechanics and chemistry of liposome interactions.

The development of long-circulating, RES-avoiding liposomes has become a remarkable milestone in the progress of contemporary pharmacology. Drugs incorporated in such liposomes are protected from fast metabolization and clearance, and can be further targeted to a desired tissue site. Ideally, future developments should result in drug carriers which can identify and act upon their targets with even higher efficiency and selectivity, preferably close to or exceeding that of the natural immune cells.

Macromolecular intravenous contrast agent for MR lymphography: characterization and efficacy studies.

Purpose: To determine the pharmacokinetic and magnetic resonance (MR) imaging properties of diethylenetriaminepentaacetic acid (DTPA) conjugated with a polyglucose-associated macrocomplex (PGM), which accumulates in lymph nodes.

Materials And Methods: In 124 normal and 20 tumor-bearing rats, Gd-DTPA PGM was administered intravenously in doses of 2, 10, 20 mumol gadolinium per kilogram of tissue.

Results: Mean blood half-life was 2 hours.

Drug delivery to lymphatic tissue.

Efficient diagnosis and therapy of diseases affecting lymph nodes rely on the availability of drugs that are retained by lymph nodes. Intralymphatically or interstitially administered macromolecular carriers accumulate efficiently in draining lymph nodes. However, because of the high variability of lymphatic networks and drainage routes, systemic administration of lymphotropic carriers would be preferable and currently represents a major focus in lymphotropic drug design.

[Presentation and quantification of acute myocardial infarct using antibody-bound MR contrast medium].

A magnetically labeled antimyosin (MION-AM) has previously been developed for immunospecific MR imaging in vivo. The current study was designed to extend previous feasibility studies and to correlate MR infarct size to that determined by histopathology. The left anterior coronary artery (LAD) was temporarily occluded in rabbits (n = 10) and subsequently reperfused for 1 h prior to the administration of 100 mumol Fe/kg of MION-AM (corresponding to 0.

MR lymphography with a lymphotropic T1-type MR contrast agent: Gd-DTPA-PGM.

A model system of a paramagnetic lymphotropic MR contrast agent (Gd-DTPA labeled polyglucose associated macrocomplex, PGM) for T1-weighted MR imaging of lymph nodes in rats and rabbits was evaluated. Pharmacokinetic (tissue accumulation) and MR imaging data (optimal dose and timing parameters) were obtained in normal rats (n = 88) after subcutaneous (SC) injection of paramagnetic, radiolabeled [111In]Gd-DTPA-PGM. A rabbit model of lymph node metastases (n = 8) was ultimately used to demonstrate the potential of MR imaging with Gd-DTPA-PGM for nodal tumor detection.

Determinants of in vivo MR imaging of slow axonal transport.

Purpose: To investigate specific surface characteristics of magnetic contrast agents based on a monocrystalline iron oxide nanoparticle (MION) that may determine their uptake and/or transport by axons.

Materials And Methods: MION were modified to have a range of surface charges or were covalently linked to wheat germ agglutinin (WGA), a neurotropic protein. Each agent was injected directly into the sciatic nerves or femoral arteries of rats (n = 22), and magnetic resonance (MR) images were obtained several days later.

Poly(ethylene glycol) on the liposome surface: on the mechanism of polymer-coated liposome longevity.

The hypothetical model is built explaining the molecular mechanism of protective action of poly(ethylene glycol) on liposomes in vivo. The protective layer of the polymer on the liposome surface is considered as a statistical 'cloud' of polymer possible conformations in solution. Computer simulation was used to demonstrate that relatively a small number of liposome-grafted molecules of hydrophilic and flexible polymer can create a dense protective conformational cloud over the liposome surface preventing opsonizing protein molecules from contacting liposome.