Cardiac retention of PET neuronal imaging agent LMI1195 in different species: impact of norepinephrine uptake-1 and -2 transporters.

Introduction: Released sympathetic neurotransmitter norepinephrine (NE) in the heart is cleared by neuronal uptake-1 and extraneuronal uptake-2 transporters. Cardiac uptake-1 and -2 expression varies among species, but the uptake-1 is the primary transporter in humans. LMI1195 is an NE analog labeled with (18)F for PET evaluation of cardiac neuronal function.

Synthesis and Cardiac Imaging of (18)F-Ligands Selective for β1-Adrenoreceptors.

A series of potent and selective β1-adrenoreceptor ligands were identified (IC50 range, 0.04-0.25 nM; β1/β2 selectivity range, 65-450-fold), labeled with the PET radioisotope fluorine-18 and evaluated in normal Sprague-Dawley rats.

Mutations in the human laminin beta2 (LAMB2) gene and the associated phenotypic spectrum.

Mutations of LAMB2 typically cause autosomal recessive Pierson syndrome, a disorder characterized by congenital nephrotic syndrome, ocular and neurologic abnormalities, but may occasionally be associated with milder or oligosymptomatic disease variants. LAMB2 encodes the basement membrane protein laminin beta2, which is incorporated in specific heterotrimeric laminin isoforms and has an expression pattern corresponding to the pattern of organ manifestations in Pierson syndrome. Herein we review all previously reported and several novel LAMB2 mutations in relation to the associated phenotype in patients from 39 unrelated families.

Cardiac imaging and safety evaluation of BMS747158, a novel PET myocardial perfusion imaging agent, in chronic myocardial compromised rabbits.

Background: BMS747158 labeled with (18)F is being developed for PET myocardial perfusion imaging. Imaging studies showed clear detection of necrotic tissue in acute myocardial infarcted (MI) animals and a good safety profile in normal animals. This study evaluated BMS747158 imaging and cardiovascular safety in a rabbit model of chronic MI with cardiac compromise.

Effects of food intake and anesthetic on cardiac imaging and uptake of BMS747158-02 in comparison with FDG.

Background: BMS747158-02 is an (18)F-labeled agent being developed for PET myocardial perfusion imaging. This study examined impacts of feeding state and anesthetic on cardiac imaging and uptake of this agent in rats in comparison with (18)F-fluorodeoxyglucose (FDG).

Methods And Results: Studies were performed in rats either nonfasted or food deprived for 20 hours and anesthetized with either sodium pentobarbital (Pentob) or ketamine and xylazine (Ket/Xyl).

Assessment of 18F-labeled mitochondrial complex I inhibitors as PET myocardial perfusion imaging agents in rats, rabbits, and primates.

Purpose: Myocardial extractions of mitochondria complex I (MC-I) inhibitors were high and well correlated with flow. This study assessed the potential of MC-I inhibitors to be developed as myocardial perfusion imaging (MPI) agents.

Methods: RP1003, RP1004, and RP1005 representing three classes of MC-I inhibitor were synthesized and radio-labeled with (18)F.

Ophthalmological aspects of Pierson syndrome.

Purpose: To study the ocular phenotype of Pierson syndrome and to increase awareness among ophthalmologists of the diagnostic features of this condition.

Design: Retrospective, observational case series.

Methods: A multicenter study of 17 patients with molecularly confirmed Pierson syndrome.

Synthesis and biological evaluation of pyridazinone analogues as potential cardiac positron emission tomography tracers.

A series of fluorinated pyridazinone derivatives with IC50 values ranging from 8 to 4000 nM for the mitochondrial complex 1 (MC1) have been prepared. Structure-activity relationship (SAR) assessment indicated preference of the fluorine label to be incorporated on an alkyl side chain rather than directly on the pyridazinone moiety. Tissue distribution studies of a series of analogues ([18F] 22-28) in Sprague-Dawley (SD) rats identified [18F]27 as the most promising radiotracer with high uptake in cardiac tissue (3.

BMS-747158-02: a novel PET myocardial perfusion imaging agent.

Background: BMS-747158-02 is a fluorine 18-labeled pyridaben derivative designed as a new myocardial perfusion imaging agent for use with positron emission tomography (PET). This study evaluated BMS-747158-02 in animal models of cardiac perfusion and compared it with established single photon emission computed tomography agents.

Methods And Results: In a rat biodistribution study, BMS-747158-02 (15 microCi) had substantially higher myocardial uptake than technetium 99m sestamibi (100 microCi) at 15 minutes (3.

Mechanism of uptake and retention of F-18 BMS-747158-02 in cardiomyocytes: a novel PET myocardial imaging agent.

Background: BMS-747158-02 is a novel fluorine 18-labeled pyridazinone derivative designed for cardiac imaging. The uptake and retention mechanisms of F-18 BMS-747158-02 in cardiac myocytes were studied in vitro, and the biodistribution of F-18 BMS-747158-02 was studied in vivo in mice.

Methods And Results: Fluorine 19 BMS-747158-01 inhibited mitochondrial complex I (MC-I) in bovine heart submitochondrial particles with an IC(50) of 16.

A milder variant of Pierson syndrome.

Congenital nephrotic syndrome (CNS) comprises a heterogeneous group of conditions having in common the disruption of normal glomerular permselectivity, and it carries a poor prognosis, with most patients progressing to end-stage renal disease. Recently, mutations in the LAMB2 gene encoding laminin beta2 were described as the cause of Pierson syndrome, which is characterized by CNS and a complex ocular maldevelopment with microcoria as the most prominent clinical features. Most affected children exhibit early onset of chronic renal failure, neurodevelopmental deficits, and blindness.

Synthesis and biological evaluation of the mitochondrial complex 1 inhibitor 2-[4-(4-fluorobutyl)benzylsulfanyl]-3-methylchromene-4-one as a potential cardiac positron emission tomography tracer.

A series of fluorinated chromone analogs with IC50 values ranging from 9 to 133 nM for the mitochondrial complex 1 (MC-I) has been prepared. A structure-activity relationship (SAR) study of the most potent fluorinated chromone analog 10 demonstrated the linkage heteroatom preference of the side chain region of the molecule while maintaining potent MC-I inhibitory activity. Tissue distribution studies 30 min after [(18)F]10 administration to Sprague-Dawley (SD) rats demonstrated high uptake of the radiotracer from the blood pool into the myocardium (2.

Quinazoline derivatives as MC-I inhibitors: evaluation of myocardial uptake using Positron Emission Tomography in rat and non-human primate.

Several quinazoline derivatives were made as mitochondrial complex 1 inhibitors. Compound 4 showed an IC(50) of 11.3 nM and was the most potent compound of this series.

Formation and evolution of structure in loop cosmology.

Inhomogeneous cosmological perturbation equations are derived in loop quantum gravity, taking into account corrections, in particular, in gravitational parts. This provides a framework for calculating the evolution of modes in structure formation scenarios related to inflationary or bouncing models. Applications here are corrections to the Newton potential and to the evolution of large scale modes which imply nonconservation of curvature perturbations possibly noticeable in a running spectral index.

Thermally induced birefringence in Faraday devices made from terbium gallium garnet-polycrystalline ceramics.

We have developed a model that describes thermally induced birefringence in polycrystalline ceramics that are exposed to a magnetic field. Conditions under which traditional compensation techniques (for glass and single crystals) can be effective for ceramics have been found. It is shown that a ceramic is almost equivalent to a [111]-oriented crystal if the ratio of the rod length to the grain size is approximately 300 or more.