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The cyclin-dependent kinase (Cdk)-cyclin D/retinoblastoma (pRb)/E2F cascade, which controls the G1/S transition of cell cycle, has been found to be altered in many neoplasias. Inhibition of this pathway by using, for example, selective Cdk4 inhibitors has been suggested to be a promising approach for cancer therapy. We hypothesized that appropriately radiolabeled Cdk4 inhibitors are suitable probes for tumor imaging and may be helpful studying cell proliferation processes in vivo by positron emission tomography. Herein, we report the synthesis and biological, biochemical, and radiopharmacological characterizations of two 124I-labeled small molecule Cdk4 inhibitors (8-cyclopentyl-6-iodo-5-methyl-2-(4-piperazin-1-ylphenylamino)-8H-pyrido[2,3-d]-pyrimidin-7-one (CKIA) and 8-cyclopentyl-6-iodo-5-methyl-2-(5-(piperazin-1-yl)-pyridin-2- yl-amino)-8H-pyrido[2,3-d]pyrimidin-7-one (CKIB)). Our data demonstrate a defined and specific inhibition of tumor cell proliferation through CKIA and CKIB by inhibition of the Cdk4/pRb/E2F pathway emphasizing potential therapeutic benefit of CKIA and CKIB. Furthermore, radiopharmacological properties of [124I]CKIA and [124I]CKIB observed in human tumor cells are promising prerequisites for in vivo biodistribution and imaging studies. [ABSTRACT FROM AUTHOR]

Abstract: Three methods for 18F-labeling of dimeric and tetrameric neurotensin(8–13) derivatives were evaluated with respect to the labeling yield and the required peptide amounts. Labeling using N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) gave low radiochemical yield for the dimeric peptides. Coupling of the tetramer with [18F]SFB was not successful. High yields were obtained for labeling of the aminooxy-functionalized neurotensin(8–13) dimer using 4-[18F]fluorobenzaldehyde ([18F]FBA) whilst coupling of the corresponding tetramer gave only low yields. Labeling of sulfydryl-functionalized neurotensin(8–13) derivatives using the maleinimide 4-[18F]fluorobenzaldehyde-O-[6-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-hexyl]-oxime ([18F]FBAM) resulted in high radiochemical yields for both, the dimer and the tetramer. Therefore, [18F]FBAM seems to be the most suitable 18F-labeling agent for multivalent neurotensin(8–13) derivatives. [Copyright &y& Elsevier]

Abstract: This work involves the production, processing and imaging of the short-lived, rarely used positron emission tomography (PET) radionuclide technetium-94m (94mTc). Our procedures are an extension of methods reported in the literature and are detailed within. A key modification was the development of a single step that combines purification and concentration of an aqueous 94mTc-pertechnetate solution, which both reduces processing time and increases the final concentration of the solution. Additionally, a convenient method for the direct recovery of 94mTc into an organic solvent was developed, eliminating the solvent transfer step needed for organic syntheses using 94mTc. Each of these advances potentially extends the scope of syntheses possible with this short-lived radionuclide. To explore the imaging potential of 94mTc, we carried out phantom imaging studies on small-scale high-resolution PET scanners to estimate the limitations of detection associated with 94mTc and PET. Preliminary studies demonstrate that useful images can be obtained with modern image reconstruction algorithms when using a correction for the cascade gamma ray contamination. [Copyright &y& Elsevier]

Abstract: Neurotensin(8–13) is a hexapeptide with subnanomolar affinity to the neurotensin receptor 1 which is expressed with high incidence in several human tumor entities. Thus, radiolabeled neurotensin(8–13) might be used for tumor targeting. However, its application is limited by insufficient metabolic stability. The present study aims at improving metabolic stability by the synthesis of multimeric neurotensin(8–13) derivatives rather than commonly employed chemical modifications of the peptide itself. Thus, different dimeric and tetrameric peptides carrying C- or N-terminal attached neurotensin(8–13) moieties have been synthesized and their binding affinity toward the neurotensin receptor has been determined. The results demonstrate that branched compounds containing neurotensin(8–13) attached via its C-terminus only show low receptor affinities, whilst derivatives with neurotensin(8–13) attached via the N-terminus show IC50 values in the nanomolar range. Moreover, within the multimeric neurotensin(8–13) derivatives with neurotensin(8–13) attached via the N-terminus an increasing number of branching units lead to higher binding affinities toward the neurotensin receptor. [Copyright &y& Elsevier]

Abstract: Oxidative modification of low-density lipoprotein (LDL) is regarded as a crucial event in atherogenesis. Assessing the metabolic fate of oxidized LDL (oxLDL) in vivo with radiotracer techniques is hindered by the lack of suitable sensitive and specific radiolabeling methods. We evaluated an improved methodology based on the radiolabeling of native LDL (nLDL) and oxLDL with the positron emitter fluorine-18 (18F) by conjugation with N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB). We investigated whether radiolabeling of LDL induces adverse structural modifications. Results suggest that radiolabeling of both nLDL and oxLDL using [18F]SFB causes neither additional oxidative structural modifications of LDL lipids and proteins nor alteration of their biological activity and functionality, respectively. Thus, radiolabeling of LDL using [18F]SFB could prove to be a promising approach for studying the kinetics of oxLDL in vivo. [Copyright &y& Elsevier]

The study describes for the first time the application of Cu(I)-mediated 1,3-dipolar [3+2]cycloaddition for the labelling of proteins with the short-lived positron emitter fluorine-18 as exemplified with azide-functionalized human serum albumin (HSA). [ABSTRACT FROM AUTHOR]

We recently showed that radiation-induced DNA damage in breast adipose tissue increases autotaxin secretion, production of lysophosphatidate (LPA) and expression of LPA1/2 receptors. We also established that dexamethasone decreases autotaxin production and LPA signaling in non-irradiated adipose tissue. In the present study, we showed that dexamethasone attenuated the radiation-induced increases in autotaxin activity and the concentrations of inflammatory mediators in cultured human adipose tissue. We also exposed a breast fat pad in mice to three daily 7.5 Gy fractions of X-rays. Dexamethasone attenuated radiation-induced increases in autotaxin activity in plasma and mammary adipose tissue and LPA1 receptor levels in adipose tissue after 48 h. DEX treatment during five daily fractions of 7.5 Gy attenuated fibrosis by ~70% in the mammary fat pad and underlying lungs at 7 weeks after radiotherapy. This was accompanied by decreases in CXCL2, active TGF-β1, CTGF and Nrf2 at 7 weeks in adipose tissue of dexamethasone-treated mice. Autotaxin was located at the sites of fibrosis in breast tissue and in the underlying lungs. Consequently, our work supports the premise that increased autotaxin production and lysophosphatidate signaling contribute to radiotherapy-induced breast fibrosis and that dexamethasone attenuated the development of fibrosis in part by blocking this process. [ABSTRACT FROM AUTHOR]

1-[4-(2-Chloroethoxy)phenyl]-5-[4-(methylsulfonyl)phenyl]-1 H -tetrazole (2) and 2-(4-(5-(4-(methylsulfonyl)phenyl)-1 H -tetrazol-1-yl)phenoxy)ethyl nitrate (3) have been easily synthesized and their molecular structure have been determined using the X-ray crystallography technique. Both tetrazoles 2 and 3 crystallize in the monoclinic space group P 2 1 /c. The cell parameters determined for tetrazole 2 are a = 25.067 (2) Å, b = 5.2236 (5) Å, c = 13.5324 (13) Å3, β = 102.3881 (13)°, V = 1730 (3) Å3, and Z = 4. Its structure refines to R 1 = 0.0654 (for 2945 observed reflections F o 2 ≥ 2 σ (F o 2)]) and w R 2 = 0.1557 (for all 4278 unique reflections). The cell dimensions for tetrazole 3 are a = 26.4012 (10) Å, b = 5.14915 (18) Å, c = 13.2950 (5) Å3, β = 92.6313 (16)°, V = 1805.47 (12) Å3, and Z = 4. Its structure refines to R 1 = 0.0329 (for 3469 observed reflections F o 2 ≥ 2 σ (F o 2)]) and w R 2 = 0.0871 (for all 3657 unique reflections). For both structures, the aryl rings at the 1- and 5-positions of the tetrazole rings show no conjugation to the tetrazole group, and intermolecular interactions between adjacent molecules are dominated by weak (2.3–2.7 Å) C–H⋯O and C–H⋯N contacts. The molecular docking studies were carried out to understand the interaction of compounds 2 and 3 within the active site of the cyclooxygenase-2 enzyme, followed by a comparison study with the celecoxib drug as a reference compound. The in vitro bioassay studies of tetrazoles 2 and 3 toward cyclooxygenase-1 and cyclooxygenase-2 enzymes showed that both compounds have no inhibition potency for either enzyme. Image 1 • The syntheses of two novel tetrazoles. • The crystal structure of tetrazole derivative and nitric oxide release azole. • The molecular docking results toward COX-2/COX-1. • The bioassay results toward COX-2/COX-1. No inhibition potency was found. [ABSTRACT FROM AUTHOR]

Breast cancer patients are usually treated with multiple fractions of radiotherapy (RT) to the whole breast after lumpectomy. We hypothesized that repeated fractions of RT would progressively activate the autotaxin–lysophosphatidate-inflammatory cycle. To test this, a normal breast fat pad and a fat pad containing a mouse 4T1 tumor were irradiated with X-rays using a small-animal "image-guided" RT platform. A single RT dose of 7.5 Gy and three daily doses of 7.5 Gy increased ATX activity and decreased plasma adiponectin concentrations. The concentrations of IL-6 and TNFα in plasma and of VEGF, G-CSF, CCL11 and CXCL10 in the irradiated fat pad were increased, but only after three fractions of RT. In 4T1 breast tumor-bearing mice, three fractions of 7.5 Gy augmented tumor-induced increases in plasma ATX activity and decreased adiponectin levels in the tumor-associated mammary fat pad. There were also increased expressions of multiple inflammatory mediators in the tumor-associated mammary fat pad and in tumors, which was accompanied by increased infiltration of CD45+ leukocytes into tumor-associated adipose tissue. This work provides novel evidence that increased ATX production is an early response to RT and that repeated fractions of RT activate the autotaxin–lysophosphatidate-inflammatory cycle. This wound healing response to RT-induced damage could decrease the efficacy of further fractions of RT. [ABSTRACT FROM AUTHOR]

Various 1,5-diaryltetrazole derivatives (II) and (V) are prepared and tested as cyclooxygenase-2 (COX-2) inhibitors. [ABSTRACT FROM AUTHOR]