Comparative breast tumor imaging and comparative in vitro metabolism of 16alpha-[18F]fluoroestradiol-17beta and 16beta-[18F]fluoromoxestrol in isolated hepatocytes

16beta-[18F]Fluoromoxestrol ([18]betaFMOX) is an analog of 16alpha-[18F]fluoroestradiol-17beta ([18F]FES), a radiopharmaceutical known to be an effective positron emission tomography (PET) imaging agent for estrogen receptor-positive (ER+) human breast tumors. Based on comparisons of target tissue uptake efficiency and selectivity in a rat model, [18F]betaFMOX was predicted to be as effective an imaging agent as [18F]FES. However, in a preliminary PET imaging study with [18F]FMOX of 12 patients, 3 of whom had ER+ breast cancer, no tumor localization of [18F]betaFMOX was observed. In search for an explanation for the unsuccessful [18F]betaFMOX clinical trial, we have examined the rate of metabolism of [18F]FMOX and [18F]FES in isolated rat, baboon, and human hepatocytes. We have also studied the effect of the serum protein sex hormone-binding globulin (SHBG), which binds [18F]FES better than [18F]betaFMOX, on these rates of metabolism. Immature rat hepatocytes were found to metabolize [18F]FES 31 times faster than [18F]betaFMOX, whereas mature rat cells metabolized [18F]FES only 3 times faster, and baboon and human hepatocytes only 2 times faster than [18F]betaFMOX. In the presence of SHBG, the metabolic consumption rate for [18F]FES in mature rat hepatocytes decreased by 26%. Thus, the very favorable target tissue uptake characteristics of [18F]betaFMOX determined in the rat probably result from its comparative resistance to metabolism (vis-a-vis [18F]FES) in this species, an advantage that is strongly reflected in comparative metabolism rates in rat hepatocytes. In the baboon and human, [18F]FES is extensively protein bound and protected from metabolism, an effect that may be reflected to a degree as a decrease in the rate of metabolism of this compound in baboon and human hepatocytes relative to [18F]betaFMOX. Thus in primates, SHBG may potentiate the ER-mediated uptake of [18F]FES in ER+ tumors by selectively protecting this ligand from metabolism and ensuring its delivery to receptor-containing cells. In addition to current screening methods for 18F-estrogens that involve evaluating in vivo ER-mediated uptake in the immature female rat, studies comparing the metabolism of the new receptor ligands in isolated hepatocytes, especially those from primates or humans, may assist in predicting the potential of these ligands for human PET imaging.     

Potential (18)F-labeled biomarkers for epidermal growth factor receptor tyrosine kinase

As PET candidate tracers for EGFr-TK, five 4-(anilino)quinazoline derivatives, each fluorinated in the aniline moiety, were prepared. Each was tested in vitro for inhibition of EGFr autophosphorylation in A431 cell line. The leading compounds were then radiolabeled with (18)F and cell binding experiments, biodistribution and PET studies in A431 tumor-bearing mice were performed. Metabolic studies were carried out in a mice control group. From our results, we concluded that while in vitro experiments indicates efficacy of 4-(anilino)quinazoline compounds, kinetic factors and rapid blood clearance make them unsuitable as tracers for nuclear medicine imaging of EGFr-TK.     

Backbone metal-cyclization: a novel approach for simultaneous peptide cyclization and radiolabeling. Application to the combinatorial synthesis of rhenium-cyclic somatostatin analogs

A novel approach for the combinatorial synthesis of backbone-derived metal-cyclic peptide libraries is presented. In this approach the metalo-cyclic peptides are prepared from their linear precursors through complexation of a metal atom via two hemi-chelating arms located on the peptide backbone. Thus, cyclization and metal labeling of the peptides are achieved simultaneously. A library, composed of 48 rhenium-cyclic somatostatin analogs, was prepared. All rhenium somatostatin complexes exhibited high to moderate in vitro binding affinities toward cloned human somatostatin receptor subtype 2 (hsstr2). Five rhenium-cyclic peptides were found to be most potent with IC50 values between 1 and 3 nM making them promising leads for further development of tumor diagnostic and therapeutic radiolabeled agents. A 99mTc somatostatin cyclic analog was successfully prepared by the same method.     

Cellular telephones measure activity and lifespace in community-dwelling adults: proof of principle

OBJECTIVES: To describe a system that uses off‐the‐shelf sensor and telecommunication technologies to continuously measure individual lifespace and activity levels in a novel way. DESIGN: Proof of concept involving three field trials of 30, 30, and 21 days. SETTING: Omaha, Nebraska, metropolitan and surrounding rural region. PARTICIPANTS: Three participants (48‐year‐old man, 33‐year‐old woman, and 27‐year‐old male), none with any functional limitations. MEASUREMENTS: Cellular telephones were used to detect in‐home position and in‐community location and to measure physical activity. Within the home, cellular telephones and Bluetooth transmitters (beacons) were used to locate participants at room‐level resolution. Outside the home, the same cellular telephones and global positioning system (GPS) technology were used to locate participants at a community‐level resolution. Physical activity was simultaneously measured using the cellular telephone accelerometer. RESULTS: This approach had face validity to measure activity and lifespace. More importantly, this system could measure the spatial and temporal organization of these metrics. For example, an individual's lifespace was automatically calculated across multiple time intervals. Behavioral time budgets showing how people allocate time to specific regions within the home were also automatically generated. CONCLUSION: Mobile monitoring shows much promise as an easily deployed system to quantify activity and lifespace, important indicators of function, in community‐dwelling adults.     

Influence of hydrocortisone on the modulation of the inflammatory response.

In vitro hydrocortisone, in pharmacologically attainable concentrations, binds nonspecifically to rat peritoneal mast cells and amplifies the stimulating effects of PGE1 on membrane-bound adenylate cyclase. As a consequence, the intracellular concentration of cyclic AMP in the target cells increases and histamine release is markedly reduced. Deoxycorticosterone, at the same concentrations, has no effect. These findings may in part explain the mechanism of action of anti-inflammatory steroids, possibly related to the modulating effects of E-type prostaglandins.     

Opuntia ficus‐indica (L.) Mill. fruit as source of betalains with antioxidant,cytoprotective, and anti‐angiogenic properties

The aim of this work was to investigate the phytochemical profile and biological properties of different colours of betalain cactus pear extracts, evaluating their antioxidant, cytoprotective, and anti‐angiogenic properties by cell‐free, cell‐based, and in vivo assays. A QuEChERS extraction method followed by RP‐LC‐DAD‐MS/MS analysis showed that indicaxanthin and betanin were the main compounds (≥94.32% and ≥96.95%, respectively). Orange cactus pear extracts exert the best antioxidant activity in all assays carried out, in particular into ORAC (17,352.55 ± 987.407 mg trolox equivalents/100 g dry weight) and β‐carotene bleaching (60.35%) assays. The red ones, instead, showed the best cytoprotective activity decreasing the cell mortality, LDH, and Caspase‐3 release ranging from 4.0 to 55%. According to antioxidant results, the orange cactus pear extracts showing also the highest anti‐angiogenic activity (IC₅₀ 19.31 μg/ml), followed by the red (IC₅₀ 23.55 μg/ml) and the yellow ones (IC₅₀ 33.97 μg/ml). In light of the results and correlation analysis, the behaviour of these molecules varies a lot according to their structure and physicochemical features and synergistic activity between betalain classes may be postulated; so the plant complex could be of greater interest compared with the isolated molecules for potential nutraceutical and pharmaceutical uses.