Search

Matrix metalloproteases (MMPs) have been found to be highly expressed in a variety of malignant tumor tissues. Noninvasive visualization of MMP activity may play an important role in the diagnosis of MMP associated diseases. Here we report the design and synthesis of a set of fluorine-19 dendron-based magnetic resonance imaging (MRI) probes for real-time imaging of MMP-2 activity. The probes have the following features: (a) symmetrical fluorine atoms; (b) the number of fluorine atoms can be increased through facile chemical modification; (c) readily accessible peptide sequence as the MMP-2 substrate; (d) activatable 19F signal (off/on mode) via paramagnetic metal ion incorporation. Following optimization for water solubility, one of the probes was selected to evaluate MMP-2 activity by 19F magnetic resonance spectroscopy (MRS). Our results showed that the fluorine signal increased by 8.5-fold in the presence of MMP-2. The specific cleavage site was verified by mass spectrometry. The selected probe was further applied to detect secreted MMP-2 activity of living SCC7 squamous cell carcinoma cells. The fluorine signal was increased by 4.8-fold by MRS analysis after 24 h incubation with SCC7 cells. This type of fluorine probe can be applied to evaluate other enzyme activities by simply tuning the substrate structures. This symmetrical fluorine dendron-based probe design extends the scope of the existing 19F MRI agents and provides a simple but robust method for real-time 19F MRI application.

Because of the important roles that matrix metalloproteinases (MMPs) play in tumor invasion and metastasis, various activatable optical probes have been developed to visualize MMP activities in vitroand in vivo. Our recently developed MMP-13 activatable probe, l-MMP-P12, has been successfully applied to image the expression and inhibition of MMPs in a xenografted tumor model [Zhu, L., et al. (2011) Theranostics 1, 18–27]. In this study, to further optimize the in vivobehavior of the proteinase activatable probe, we tracked and profiled the metabolites by a high-resolution liquid chromatography–mass spectrometry (LC–MS) system. Two major metabolites that contributed to the fluorescence recovery were identified. One was specifically cleaved between glycine (G4) and valine (V5) by MMP, while the other one was generated by nonspecific cleavage between glycine (G7) and lysine (K8). To visualize the MMP activity more accurately and specifically, a new probe, d-MMP-P12, was designed by replacing the l-lysine with d-lysine in the MMP substrate sequence. The metabolic profile of the new probe, d-MMP-P12, was further characterized by in vitroenzymatic assay, and no nonspecific metabolite was found by LC–MS. Our in vivooptical imaging also demonstrated that d-MMP-P12 had a tumor-to-background ratio (TBR, 5.55 ± 0.75) significantly higher than that of l-MMP-P12 (3.73 ± 0.31) 2 h postinjection. The improved MMP activatable probe may have the potential for drug screening, tumor diagnosis, and therapy response monitoring. Moreover, our research strategy can be further extended to study other protease activatable probes.

Therapy for human immunodeficiency virus HIVinfected patients requires chronic multidrug administration. The eventual failure of therapy in some patients has brought into question the tissue concentration of the drugs. With an appropriately radiolabeled compound, we could utilize positron emission tomography to provide quantitative time–activity curves for various tissues. We have developed a fluorine18 labeled analog of Tenofovir, the active metabolite of Tenofovir DF, a commonly prescribed component of multidrug therapy. Because 16amino9Hpurin9yl3fluoropropan2yloxymethylphosphonic acid FPMPA has a chiral center, we prepared both enantiomers and confirmed that the Sisomer exhibited significantly higher antiviral activity than the Risomer. In viral replication inhibition assays in human MT4 cells infected with SHIVDH12R, SFPMPA had an IC50of 1.85 µM 95 CI; 0.8–5.53, while the Risomer was inactive. An appropriate chiral precursor was prepared to allow the incorporation of fluorine18. The 18FFPMPA in racemic, R, or S form was prepared in a 50 min synthesis in 38±5 yield n23, corrected for decay. The product was of high radiochemical and enantiomeric purity. The specific activity of the final product was 4.0±1.8 Ciµmol at EOB end of bombardment. This product may provide information about drug tissue distribution in animal models under chronic drug treatment. Copyright © 2008 John Wiley & Sons, Ltd.

Radiopharmaceuticals containing an ¹⁸F label are of increasing interest due to their utilization in PET imaging. However, the bottleneck in these applications is the limited methods available for introduction of this radionuclide into biologically interesting molecules. In this work, we have evaluated a new radiofluorination method based on the properties of the complex between 1,8-(dimethylamino)-naphthalene (PS) and [¹⁸F]–HF. The results obtained on various model substrates suggest that, in some limited cases, this new procedure can be regarded as a possible alternative to the traditional nucleophilic route using K222/K2CO3 in CH3CN. Copyright © 2004 John Wiley & Sons, Ltd.

Abextide, synthesized by conjugating an albumin‐binding moiety—truncated Evans blue—to glucagon‐like peptide 1 receptor (GLP‐1R) agonist exendin‐4, shows extended drug release and enhanced hypoglycemic effect in diabetic mice. The aim of this study is to evaluate the pharmacodynamics of Abextide in nonhuman primates. Two batches of elderly cynomolgus monkeys with naturally occurring diabetes are used for this study. During the whole experiment period, no abnormalities such as swelling at the injection site, lethargy, or hypoglycemia are observed in all animals. The monkeys in the Abextide group lose appetite after drug administration and then recover over time. In the single dose treatment, at day 1 and day 3 after treatment, decreased plasma glucose level is observed in the Abextide‐treated group but not in placebo or Albiglutide‐treated group. For monkeys that receive two doses of drug, the blood glucose level in all subjects in Abextide group decreases rapidly upon drug administration and return to a plateau by day 3. A similar pattern of response is seen after the second dose administration. The delayed drug release and hypoglycemic effect of Abextide make it potentially useful as an antidiabetic drug for weekly subcutaneous administration. A long‐lasting and long‐acting exendin‐4 analogue,Abextide, is developed by conjugating GLP1R agonist exendin‐4 and a truncated Evans blue as the albumin‐binding moiety. Significantly decreased plasma glucose level is observed in Abextide‐treated group. No severe side effect is identified in treated animals. Abextide is a promising candidate as an antidiabetic drug for weekly subcutaneous administration.

Review: 39 refs.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.