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A series of mono- and bis-polyethylene glycol (PEG)-substituted BF2-azadipyrromethene fluorophores have been synthesized with emissions in the near-infrared region (700–800 nm) for the purpose of fluorescence guided intraoperative imaging; chiefly ureter imaging. The Bis-PEGylation of fluorophores resulted in higher aqueous fluorescence quantum yields, with PEG chain lengths of 2.9 to 4.6 kDa being optimal. Fluorescence ureter identification was possible in a rodent model with the preference for renal excretion notable through comparative fluorescence intensities from the ureters, kidneys and liver. Ureteral identification was also successfully performed in a larger animal porcine model under abdominal surgical conditions. Three tested doses of 0.5, 0.25 and 0.1 mg/kg all successfully identified fluorescent ureters within 20 min of administration which was sustained up to 120 min. 3-D emission heat map imaging allowed the spatial and temporal changes in intensity due to the distinctive peristaltic waves of urine being transferred from the kidneys to the bladder to be identified. As the emission of these fluorophores could be spectrally distinguished from the clinically-used perfusion dye indocyanine green, it is envisaged that their combined use could be a step towards intraoperative colour coding of different tissues. [ABSTRACT FROM AUTHOR]

The scope of a tandem conjugate addition-fluorination sequence performed on [alpha],[beta]-unsaturated esters by using the enantiopure lithium amide derived from (S)-N-benzyl-N-([alpha]-methylbenzyl)amine, and the electrophilic fluorinating agent N-fluorobenzenesulfonimide is examined. The method is used for preparing enantiopure [alpha]-fluoro-[[beta].sup.3]-amino acids and its utility is shown by the preparation of orthogonally protected (2S,3S)-[alpha]-fluoro-[[beta].sup.3]-lysine.

The synthesis of a set of monofluorinated, difluorinated, and non-fluorinated N-acetylated-α[sup 3]-arginine esters, potential inhibitors of trypsin-like proteases, is described. Elaboration to the target compounds from previously reported enantiopure precursors derived from 3-hydroxypropanal involved 6-7 steps and was achieved in 48-65 % overall yield. The α,α-difluoro-β[sup 3]-arginine derivative was found to be particularly prone to hydrolysis. Three β[sup 3]-arginine derivatives were tested for their ability to inhibit trypsin, the a,α-difluoro compound being assayed in the form of a carboxylate zwitterion. [ABSTRACT FROM AUTHOR]

Background: Combining modalities using dual-labeled antibodies may allow preoperative and intraoperative tumor localization and could be used in image-guided surgery to improve complete tumor resection. Trastuzumab is a monoclonal antibody against the human epidermal growth factor-2 (HER2) receptor and dual-labeled trastuzumab with both a fluorophore (IRDye800CW) and a radioactive label (111In) can be used for multimodal imaging of HER2-positive breast cancer. The aim of this study was to demonstrate the feasibility of HER2-targeted multimodal imaging using [111In]In-DTPA-trastuzumab-IRDye800CW in an orthotopic breast cancer model. Methods: Trastuzumab was conjugated with p-isothiocyanatobenzyl (ITC)-diethylenetriaminepentaacetic acid (DTPA) and IRDye800CW-NHS ester and subsequently labeled with 111In. In a dose escalation study, the biodistribution of 10, 30, and 100 μg [111In]In-DTPA-trastuzumab-IRDye800CW was determined 48 h after injection in BALB/c nude mice with orthotopic high HER2-expressing tumors. Also, a biodistribution study was performed in a low HER2-expressing breast cancer model. In addition, multimodal image-guided surgery was performed in each group. Autoradiography, fluorescence microscopy, and immunohistochemically stained slices of the tumors were compared for co-localization of tumor tissue, HER2 expression, fluorescence, and radiosignal. Results: Based on the biodistribution data, a 30 μg dose of dual-labeled trastuzumab (tumor-to-blood ratio 13 ± 2) was chosen for all subsequent studies. [111In]In-DTPA-trastuzumab-IRDye800CW specifically accumulated in orthotopic HER2-positive BT474 tumors (101 ± 7 %IA/g), whereas uptake in orthotopic low HER2-expressing MCF7 tumor was significantly lower (1.2 ± 0.2 %IA/g, p = 0.007). BT474 tumors could clearly be visualized with both micro-SPECT/CT, fluorescence imaging and subsequently, image-guided resection was performed. Immunohistochemical analyses of BT474 tumors demonstrated correspondence in fluorescence, radiosignal, and high HER2 expression. Conclusions: Dual-labeled trastuzumab showed specific accumulation in orthotopic HER2-positive BT474 breast tumors with micro-SPECT/CT and fluorescence imaging and enabled image-guided tumor resection. In the clinical setting, [111In]In-DTPA-trastuzumab-IRDye800CW could be valuable for preoperative detection of (metastatic) tumors by SPECT/CT imaging, and intraoperative localization by using a gamma probe and fluorescence image-guided surgery to improve radical resection of tumor tissue in patients with HER2-positive tumors. [ABSTRACT FROM AUTHOR]

(R)-2-Phenylglycine ethyl ester was found to be a cheap and effective auxiliary for the preparation of aliphatic α,α-difluoro-β(3)-amino esters via a Reformatsky reaction performed under sonication conditions. The products were obtained in good to high yield and ≥96:4 dr, thus providing a new stereoselective route to this under-represented class of compounds. A facile one-pot removal of the phenylglycine moiety and concomitant Boc protection subsequently afforded the corresponding Boc-protected β(3)-amino esters in excellent yield., (© 2011 American Chemical Society)