Synthesis and evaluation of (S)-2-(2-[18F]fluoroethoxy)-4-([3-methyl-1-(2-piperidin-1-yl-phenyl)-butyl-carbamoyl]-methyl)-benzoic acid ([18F]repaglinide): a promising radioligand for quantification of pancreatic β-cell mass with positron emission tomography (PET)

18F-labeled non-sulfonylurea hypoglycemic agent (S)-2-(2-[(18)F]fluoroethoxy)-4-((3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl)-methyl)-benzoic acid ([(18)F]repaglinide), a derivative of the sulfonylurea-receptor (SUR) ligand repaglinide, was synthesized as a potential tracer for the non-invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta-cells by positron emission tomography (PET) in the context of type 1 and type 2 diabetes. [(18)F]Repaglinide could be obtained in an overall radiochemical yield (RCY) of 20% after 135 min with a radiochemical purity higher than 98% applying the secondary labeling precursor 2-[(18)F]fluoroethyltosylate. Specific activity w…

Synthesis and in vitro evaluation of (S)-2-([11C]methoxy)-4-[3-methyl-1-(2-piperidine-1-yl-phenyl)-butyl-carbamoyl]-benzoic acid ([11C]methoxy-repaglinide): a potential beta-cell imaging agent.

The 11 C-labeled sulfonylurea receptor 1 (SUR1) ligand (S)-2-(( 11 C)methoxy)-4-(3-methyl-1-(2-piperidine-1-yl-phenyl)- butyl-carbamoyl)-benzoic acid (( 11 C)methoxy-repaglinide) was synthesized in an overall radiochemical yield of 35% after 55 min with a radiochemical purity higher than 99%. This compound is considered for the noninvasive investigation of the SUR1 receptor status of pancreatic b-cells by positron emission tomography (PET) in the context of type 1 and type 2 diabetes. The specific activity was 40-70 GBq/lmol. In vitro testing of the nonradioactive methoxy-repaglinide was performed to characterize the affinity for binding to the human SUR1 isoform. Methoxy-repaglinide induce…

Synthesis and first evaluation of new 18F-labelled sulfonylureas for the determination of the beta-cell status in vivo

The syntheses and first in vitro evaluations for two fluoride bearing sulfonylurea derivatives are reported. Firstly, the tolbutamide derivative 1-[4-(2-[18F]fluoroethoxy)benzenesulfonyl]-3-butyl urea (2-[18F]fluoroethyl-tolbutamide) could be labeled efficiently with [18F]fluoride. Subsequently, the glibenclamid derivative N-(2-(4-(N-((cyclohexylamino)carbonyl)sulfonylamino)phenyl)ethyl) 2-(5-chloro-2-[18F]fluorethoxy)phenyl) formamide (2-[18F]fluoroethyl-glibenclamide) was labeled with [18F]fluoride in high yields. Its ability to induce insuline secretion from rat beta-cells in relation to the original glibenclamide was determined.

Magnetic separation of encapsulated islet cells labeled with superparamagnetic iron oxide nano particles.

Islet cell transplantation is a promising option for the restoration of normal glucose homeostasis in patients with type 1 diabetes. Because graft volume is a crucial issue in islet transplantations for patients with diabetes, we evaluated a new method for increasing functional tissue yield in xenogeneic grafts of encapsulated islets. Islets were labeled with three different superparamagnetic iron oxide nano particles (SPIONs; dextran-coated SPION, siloxane-coated SPION, and heparin-coated SPION). Magnetic separation was performed to separate encapsulated islets from the empty capsules, and cell viability and function were tested. Islets labeled with 1000 μg Fe/ml dextran-coated SPIONs expe…

Intraportal transplantation of allogenic pancreatic islets encapsulated in barium alginate beads in diabetic rats.

The survival of microencapsulated islets transplanted into the unmodified peritoneal cavity is limited, even if capsular overgrowth is restricted to a minimum, due to an insufficient oxygen supply to the islets. Therefore, research efforts should focus on finding or creating a transplantation site, which permits a closer contact between the encapsulated islets and the blood. For this reason, the liver could be an interesting candidate. The aim of the present study was to test the hypothesis that the intraportal transplantation of allogenic islets encapsulated in small-sized barium alginate beads is safe and succeeds to induce normoglycemia in diabetic rats. The intraportal transplantation o…

Biocompatibility of alginates for grafting: impact of alginate molecular weight.

Optimising microencapsulation technology towards the effective clinical transplantation has created the need for highly biocompatible alginates. Therefore, in this study the biocompatibility of different beads prepared from alginates with varying average molecular weight was examined. In some experiments the beads were covered with a multilayer membrane surrounded by an alginate layer. First of all, we found that beads made of a lower weight average alginate elicted a much stronger fibrotic response compared to beads made of a higher weight average alginate (LV-alginate > MV-alginate). The results were confirmed by the observation that the extent of tissue fibrosis was significantly increas…

Long-term graft function of adult rat and human islets encapsulated in novel alginate-based microcapsules after transplantation in immunocompetent diabetic mice.

We describe the results of the first study to show that adult rat and human islets can be protected against xenogenic rejection in immunocompetent diabetic mice by encapsulating them in a novel alginate-based microcapsule system with no additional permselective membrane. Nonencapsulated islets lost function within 4–8 days after being transplanted into diabetic Balb/c mice, whereas transplanted encapsulated adult rat or human islets resulted in normoglycemia for >7 months. When rat islet grafts were removed 10 and 36 weeks after transplantation, the mice became immediately hyperglycemic, thus demonstrating the efficacy of the encapsulated islets. The explanted capsules showed only a …

Radiosynthesis of 1-(4-(2-[18F]fluoroethoxy)benzenesulfonyl)-3-butyl urea: a potentialβ-cell imaging agent

Summary Tolbutamide (1) is a sulfonurea agent used to stimulate insulin secretion in type 2 diabetic patients. Its analogue 1-(4-(2-[ 18 F]fluoroethoxy)benzenesulfonyl)-3butyl urea (3) was synthesized in overall radiochemical yields of 45% as a potential b-cell imaging agent. Compound 3 was synthesized by 18 F-fluoroalkylation of the corresponding hydroxy precursor (2 )w ith 2-[ 18 F]fluoroethyltosylate in DMF at 1208C for 10 min followed by purification with HPLC in a synthesis time of 50 min. Insulin secretion experiments of the authentic 19 F-standard compound on rat islets showed that the compound has a similar stimulating effect on insulin secretion as that of tolbutamide (1). The part…

Alginate encapsulation improves viability and integrity of cryopreserved pancreatic islets and multicellular spheroids: combined fluorescence, scanning and block-face scanning electron microscopy

Extended abstract of a paper presented at MC 2007, 33rd DGE Conference in Saarbrücken, Germany, September 2 – September 7, 2007

Hepatocytes cultured in alginate microspheres: an optimized technique to study enzyme induction.

An important application of hepatocyte cultures is identification of drugs acting as inducers of biotransformation enzymes that alter metabolic clearance of other therapeutic agents. In the present study we optimized an in vitro system with hepatocytes cultured in alginate microspheres that allow studies of enzyme induction with excellent sensitivity. Induction factors obtained with standard inducers, such as 3-methylcholanthrene or phenobarbital, were higher compared to those with conventional hepatocyte co-cultures on collagen coated dishes. This is illustrated by activities of 7-ethoxyresorufin-O-deethylase (EROD) after incubation with 5 microM 3-methylcholanthrene (3-MC), a standard ind…

Synthesis and in vitro Evaluation of (S)-2-([11C]Methoxy)-4- [3-methyl-1-(2-piperidine-1-yl-phenyl)-butyl-carbamoyl]-benzoic Acid ([11C]Methoxy-repaglinide): A Potential ?-Cell Imaging Agent.

Multilayer capsules: a promising microencapsulation system for transplantation of pancreatic islets

In 1980, Lim and Sun introduced a microcapsule coated with an alginate/polylysine complex for encapsulation of pancreatic islets. Characteristic to this type of capsule is, that it consists of a plain membrane which is formed during a single procedural step. With such a simple process it is difficult to obtain instantly a membrane optimized with respect to all the properties requested for islet transplantation. To overcome these difficulties, it is recommended to build up the membrane in several consecutive steps, each optimized for a certain property. In this study, we have analysed such a multilayer microcapsule for the encapsulation of pancreatic islets. Therefore, empty and islet contai…