Validation of the standardization framework SSTR-RADS 1.0 for neuroendocrine tumors using the novel SSTR­targeting peptide [18F]SiTATE.

OBJECTIVES: Somatostatin receptor positron emission tomography/computed tomography (SSTR-PET/CT) using [68Ga]-labeled tracers is a widely used imaging modality for neuroendocrine tumors (NET). Recently, [18F]SiTATE, a SiFAlin tagged [Tyr3]-octreotate (TATE) PET tracer, has shown great potential due to favorable clinical characteristics. We aimed to evaluate the reproducibility of Somatostatin Receptor-Reporting and Data System 1.0 (SSTR-RADS 1.0) for structured interpretation and treatment planning of NET using [18F]SiTATE. METHODS: Four readers assessed [18F]SiTATE-PET/CT of 95 patients according to the SSTR-RADS 1.0 criteria at two different time points. Each reader evaluated up to five target lesions per scan. The overall scan score and the decision on peptide receptor radionuclide therapy (PRRT) were considered. Inter- and intra-reader agreement was determined using the intraclass correlation coefficient (ICC). RESULTS: The ICC analysis on the inter-reader agreement using SSTR-RADS 1.0 for identical target lesions (ICC ≥ 85%), overall scan score (ICC ≥ 90%), and the decision to recommend PRRT (ICC ≥ 85%) showed excellent agreement. However, significant differences were observed in recommending PRRT among experienced readers (ER) (p = 0.020) and inexperienced readers (IR) (p = 0.004). Compartment-based analysis demonstrated good to excellent inter-reader agreement for most organs (ICC ≥ 74%), except for lymph nodes (ICC ≥ 53%). CONCLUSION: SSTR-RADS 1.0 represents a highly reproducible and consistent framework system for stratifying SSTR-targeted PET/CT scans, even using the novel SSTR-ligand [18F]SiTATE. Some inter-reader variability was observed regarding the evaluation of uptake intensity prior to PRRT as well as compartment scoring of lymph nodes, indicating that those categories require special attention during further clinical validation and might be refined in a future SSTR-RADS version 1.1. CLINICAL RELEVANCE STATEMENT: SSTR-RADS 1.0 is a consistent framework for categorizing somatostatin receptor-targeted PET/CT scans when using [18F]SiTATE. The framework serves as a valuable tool for facilitating and improving the management of patients with NET. KEY POINTS: SSTR-RADS 1.0 is a valuable tool for managing patients with NET. SSTR-RADS 1.0 categorizes patients with showing strong agreement across diverse reader expertise. As an alternative to [68Ga]-labeled PET/CT in neuroendocrine tumor imaging, SSTR-RADS 1.0 reliably classifies [18F]SiTATE-PET/CT.

Biodistribution and first clinical results of 18F-SiFAlin-TATE PET: a novel 18F-labeled somatostatin analog for imaging of neuroendocrine tumors.

INTRODUCTION: PET/CT using 68Ga-labeled somatostatin analogs (SSA) targeting somatostatin receptors (SSR) on the cell surface of well-differentiated neuroendocrine tumors (NET) represents the clinical reference standard for imaging. However, economic and logistic challenges of the 68Ge/68Ga generator-based approach have disadvantages over 18F-labeled compounds. Here, we present the first in-human data of 18F-SiFAlin-TATE, a novel 18F-labeled, SSR-targeting peptide. The aim was to compare the intra-individual biodistribution, tumor uptake, and image quality of 18F-SiFAlin-TATE to the clinical reference standard 68Ga-DOTA-TOC. METHODS: Thirteen patients with NET staged with both 68Ga-DOTA-TOC and 18F-SiFAlin-TATE PET/CT have been included in this retrospective analysis. We compared the biodistribution in normal organs and tumor uptake of NET lesions by SUVmean and SUVmax measurement for tracers. Additionally mean and max tumor-to-liver (TLR) and tumor-to-spleen ratios (TSR) have been calculated by division of SUVmean and SUVmax of tumor lesions by the SUVmean of the liver and spleen, respectively. Additionally, image quality was visually rated by 5 blinded readers and an intra-class correlation (ICC) analysis on inter-observer agreement has been performed. RESULTS: Compared with 68Ga-DOTA-TOC, the biodistribution of 18F-SiFAlin-TATE showed somewhat higher, however, statistically not significant higher uptake in the liver, spleen, and adrenal glands. Significantly higher uptake was observed in the kidneys. Tumor uptake was higher in most tumor lesions with significantly higher uptake in common metastatic sites of NET including the liver (SUVmax 18.8 ± 8.4 vs. 12.8 ± 5.6; p < 0.001), lymph nodes (SUVmax 23.8 ± 20.7 vs. 17.4 ± 16.1; p < 0.001) and bone (SUVmax 16.0 ± 10.1 vs. 10.3 ± 5.7; p < 0.01) for 18F-SiFAlin-TATE. The high tumor uptake resulted in favorable TLR and TSR, comparable with that of 68Ga-DOTA-TOC. The ICC analysis on the inter-observer agreement on image quality was substantial and almost perfect. Image quality was rated as excellent in most cases in both 68Ga-DOTA-TOC and 18F-SiFAlin-TATE PET. CONCLUSION: The favorable characteristics of 18F-SiFAlin-TATE with a high image quality, the kit-like labeling procedure, and the promising clinical performance enable improved logistics and diagnostic possibilities for PET imaging of NET. Our first clinical results warrant further systematic studies investigating the clinical use of 18F-SiFAlin-TATE in NET patients.

Next Generation of SiFAlin-Based TATE Derivatives for PET Imaging of SSTR-Positive Tumors: Influence of Molecular Design on In Vitro SSTR Binding and In Vivo Pharmacokinetics.

The Silicon-Fluoride-Acceptor (SiFA)-(18)F-labeling strategy has been shown before to enable the straightforward and efficient (18)F-labeling of complex biologically active substances such as proteins and peptides. Especially in the case of peptides, the radiolabeling proceeds kit-like in short reaction times and without the need of complex product workup. SiFA-derivatized, (18)F-labeled Tyr(3)-octreotate (TATE) derivatives demonstrated, besides strong somatostatin receptor (SSTR) binding, favorable in vivo pharmacokinetics as well as excellent tumor visualization by PET imaging. In this study, we intended to determine the influence of the underlying molecular design and used molecular scaffolds of SiFAlin-TATE derivatives on SSTR binding as well as on the in vivo pharmacokinetics of the resulting (18)F-labeled peptides. For this purpose, new SiFAlin-(Asp)n-PEG1-TATE analogs (where n = 1-4) were synthesized, efficiently radiolabeled with (18)F in a kit-like manner and obtained in radiochemical yields of 70-80%, radiochemical purities of ≥97%, and nonoptimized specific activities of 20.1-45.2 GBq/µmol within 20-25 min starting from 0.7-1.5 GBq of (18)F. In the following, the radiotracer's lipophilicities and stabilities in human serum were determined. Furthermore, the SSTR-specific binding affinities were evaluated by a competitive displacement assay on SSTR-positive AR42J cells. The obtained in vitro results support the assumption that aspartic acids are able to considerably increase the radiotracer's hydrophilicity and that their number does not affect the SSTR binding potential of the TATE derivatives. The most promising tracer (18)F-SiFAlin-Asp3-PEG1-TATE [(18)F]6 (LogD = -1.23 ± 0.03, IC50 = 20.7 ± 2.5 nM) was further evaluated in vivo in AR42J tumor-bearing nude mice via PET/CT imaging against the clinical gold standard (68)Ga-DOTATATE as well as the previously developed SiFAlin-TATE derivative [(18)F]3. The results of these evaluations showed that [(18)F]6-although showing very similar chemical and in vitro properties to [(18)F]3-exhibits not only a slowed renal clearance compared to [(18)F]3, but also a higher absolute tumor uptake compared to (68)Ga-DOTATATE, and furthermore enables excellent tumor visualization with high image resolution. These results emphasize the importance of systematic study of the influence of molecular design and applied structure elements of peptidic radiotracers, as these may considerably influence in vivo pharmacokinetics while not affecting other parameters such as radiochemistry, lipophilicity, serum stability, or receptor binding potential.

Next Step toward Optimization of GRP Receptor Avidities: Determination of the Minimal Distance between BBN(7-14) Units in Peptide Homodimers.

As the gastrin releasing peptide receptor (GRPR) is overexpressed on several tumor types, it represents a promising target for the specific in vivo imaging of these tumors using positron emission tomography (PET). We were able to show that PESIN-based peptide multimers can result in substantially higher GRPR avidities, highly advantageous in vivo pharmacokinetics and tumor imaging properties compared to the respective monomers. However, the minimal distance between the peptidic binders, resulting in the lowest possible system entropy while enabling a concomitant GRPR binding and thus optimized receptor avidities, has not been determined so far. Thus, we aimed here to identify the minimal distance between two GRPR-binding peptides in order to provide the basis for the development of highly avid GRPR-specific PET imaging agents. We therefore synthesized dimers of the GRPR-binding bombesin analogue BBN(7-14) on a dendritic scaffold, exhibiting different distances between both peptide binders. The homodimers were further modified with the chelator NODAGA, radiolabeled with (68)Ga, and evaluated in vitro regarding their GRPR avidity. We found that the most potent of the newly developed radioligands exhibits GRPR avidity twice as high as the most potent reference compound known so far, and that a minimal distance of 62 bond lengths between both peptidic binders within the homodimer can result in concomitant peptide binding and optimal GRPR avidities. These findings answer the question as to what molecular design should be chosen when aiming at the development of highly avid homobivalent peptidic ligands addressing the GRPR.

Automated radiosynthesis of N-succinimidyl 3-(di-tert-butyl[(18)F]fluorosilyl)benzoate ([(18)F]SiFB) for peptides and proteins radiolabeling for positron emission tomography.

Recently, silicon fluoride building blocks (SiFA) have emerged as valuable and promising tools to overcome challenges in the labeling of peptides and proteins for positron emission tomography (PET). Herein, we report a fully automated synthesis of N-succinimidyl 3-(di-tert-butyl[(18)F]fluorosilyl)benzoate ([(18)F]SiFB) by a commercially available Scintomics Hot Box 3 synthesis module, to be used as a prosthetic group for peptide and protein labeling. The drying of K2.2.2./K (18)F complex was performed according to the Munich method modified by our group (avoiding azeotropic drying) using oxalic acid to neutralize the base from the (18)F(-) containing QMA eluent. This K2.2.2./K (18)F complex was then used for SiFA (18)F-(19)F isotopic exchange followed by a fast purification by a solid-phase-extraction (SPE) to afford [(18)F]SiFB with an average preparative radiochemical yield (RCY) of 24±1% (non-decay corrected (NDC)) within a synthesis time of 30 min. The [(18)F]SiFB produced by automated synthesis was then used for the (18)F-labeling of rat serum albumin (RSA) as a proof of applicability.

Physician health programmes and malpractice claims: reducing risk through monitoring.

BACKGROUND: Physician health programmes (PHPs) are peer-assistance organizations that provide support to physicians struggling with addiction or with physical or mental health challenges. While the services they offer are setting new standards for recovery and care, they are not immune to public debate and criticism since some have concerns about those who are enrolled in, or have completed, such programmes and their subsequent ability to practice medicine safely. AIMS: To examine whether medical malpractice claims were associated with monitoring by a PHP using a retrospective examination of administrative data. METHODS: Data on PHP clients who were insured by the largest malpractice carrier in the state were examined. First, a business-model analysis of malpractice risk examined relative risk ratings between programme clients and a matched physician cohort. Second, Wilcoxon analysis examined differences in annual rates of pre- and post-monitoring claims for PHP clients only. RESULTS: Data on 818 clients was available for analysis. After monitoring, those enrolled in the programme showed a 20% lower malpractice risk than the matched cohort. Furthermore physicians' annual rate of claims were significantly lower after programme monitoring among PHP clients (P < 0.01). CONCLUSIONS: This is the only study examining this issue to date. While there are a variety of reasons why physicians present to PHPs, this study demonstrates that treatment and monitoring is associated with a lowered risk of malpractice claims and suggests that patient care may be improved by PHP monitoring.

Chelating agents and their use in radiopharmaceutical sciences.

Radiometal nuclides can serve as diagnostic markers in molecular imaging or can be used in therapeutic settings for a rising number of human afflictions. For the targeted delivery of these medically interesting ions, appropriate chelating agents forming stable complexes are of fundamental importance. For different metal ions exhibiting different physical and chemical properties, resulting in different coordination chemistries and therefore differing requirements on the chelator used, a broad variety of chelating agents has been developed over the years. Not only the chemical properties of the metal ion determine the choice of the chelator, but also the desired in vivo behavior of the resulting molecular imaging or therapeutic compound influences the choice of the complexation agent. Furthermore, the conjugation chemistry for the introduction of the chelator into the biologically active compound and the complexation reaction of the metal ion can affect the choice of the appropriate chelator. This review outlines chelating agents used in medicinal chemistry, their radiometal complexation behavior and their potential influence on the properties of the resulting drugs.

In vivo molecular imaging of somatostatin receptors in pancreatic islet cells and neuroendocrine tumors by miniaturized confocal laser-scanning fluorescence microscopy.

The aim of the study was to evaluate real time in vivo molecular imaging of somatostatin receptors (sstrs) using a handheld miniaturized confocal laser scan microscope (CLM) in conjunction with fluorescein-labeled octreotate (OcF) in healthy mice and murine models of neuroendocrine tumors. For CLM a small rigid probe (diameter 7 mm) with an integrated single line laser (488 nm) was used (optical slice thickness 7 mum; lateral resolution 0.7 mum). OcF was synthesized via Fmoc solid-phase peptide synthesis and purified by HPLC showing high-affinity binding to the sstr2 (IC(50) 6.2 nmol). For in vitro evaluation, rat and human pancreatic cancer cells were used and characterized with respect to its sstr subtype expression and functional properties. For in vivo confocal imaging, healthy mouse pancreatic islet and renal tubular cells as well as immunoincompetent nude mice harboring sstr-expressing tumors were evaluated. Incubation of sstr-positive cells with OcF showed a specific time- and dose-dependent staining of sstr-positive cells. CLM showed rapid internalization and homogenous cytoplasmatic distribution. After systemic application to mice (n = 8), specific time-dependent internalization and cytoplasmatic distribution into pancreatic islet cells and tubular cells of the renal cortex was recorded. After injection in tumor-harboring nude mice (n = 8), sstr-positive cells selectively displayed a cell surface and cytoplasmatic staining. CLM-targeted biopsies detected sstr-positive tumor cells with a sensitivity of 87.5% and a specificity of 100% as correlated with ex vivo immunohistochemistry. CLM with OcF permits real-time molecular, functional, and morphological imaging of sstr-expressing cell structures, allowing the specific visualization of pancreatic islet cells and neuroendocrine tumors in vivo.

Click-chemistry reactions in radiopharmaceutical chemistry: fast & easy introduction of radiolabels into biomolecules for in vivo imaging.

Today the term "click chemistry" is often used equivalent with the copper-catalyzed 1,3-dipolar Huisgen cycloaddition. Originally, the concept was introduced in 2001 to describe reactions fulfilling a set of criteria that are most useful for chemical syntheses in drug research. In radiopharmaceutical chemistry where short lived radioisotopes are introduced into various different substance classes for in vivo imaging of biochemical processes, the expanding field of radioactive bioconjugation has become predominant. Labeled biomolecules such as peptides, proteins and oligonucleotides generated via bioconjugation of chelators for radiometal introduction as well as novel valuable secondary precursors for (18)F labeling have enriched the growing field of molecular imaging substantially. When introducing radioactive nuclides with a very short half-life into biomolecules, some of the typical criteria defined by click-chemistry are more crucial than others. Time is always the most important issue, whereas avoiding the formation of by-products that have to be removed without chromatography is of minor importance. The short-lived radionuclide (11)C for example has a physical half-life of only 20 min so that the labeling procedure cannot exceed 40-60 minutes (2-3 half-lifes). In this contribution, we outline reactions and molecules which meet the requirements of click chemistry reactions and are suitable for radiosyntheses of short lived SPECT ((99m)Tc: t(1/2) = 6 h, (111)In: t(1/2) = 2.81 d) and PET ((11)C: t(1/2) = 20.3 min to (64)Cu: t(1/2) = 12.7 h) radiotracers for in vivo imaging of biological processes and review the contributions in the field of radiochemical "click-reactions" - 1,3-dipolar Huisgen cycloadditions and beyond.

Time-efficient and convenient synthesis of [(18)F]altanserin for human PET imaging by a new work-up procedure.

[(18)F]Altanserin, an important PET radioligand for the in vivo imaging of the 5-HT(2A) receptor, was synthesized from its precursor nitro-altanserin in DMF or DMSO at high temperatures of 150 degrees C in an overall radiochemical yield (EOB) of 23-25% after 75min. A new solid phase work-up procedure involving the acidification of the crude reaction mixture and a C18-SepPak-solid phase separation preceded the final HPLC purification. This led to a significantly reduced synthesis time as a result of a stable and early elution from the HPLC column using improved HPLC conditions (MeOH/THF/NaOAc 0.05N pH 5: 27/18/55, flow: 5 mL/min, Symetry Prep 7 microm C18 (Waters)). The synthesis was performed semi-automatically in a modified GE TracerLab synthesis module using an in-house-developed program. The synthesized [(18)F]altanserin was used in our ongoing human and animal PET imaging studies.

In-vivo confocal real-time mini-microscopy in animal models of human inflammatory and neoplastic diseases.

BACKGROUND AND STUDY AIMS: Although various improvements in tissue imaging modalities have recently been achieved, in-vivo molecular and subsurface imaging in the field of gastroenterology remains a technical challenge. In this study we evaluated a newly developed, handheld, miniaturized confocal laser microscopy probe for real-time in-vivo molecular and subsurface imaging in rodent models of human disease. MATERIALS AND METHODS: The minimicroscope uses a 488-nm, single line laser for fluorophore excitation. The optical slice thickness is 7 microm, the lateral resolution 0.7 microm. The range of the z-axis is 0-250 microm below the tissue surface. Imaging was performed using different fluorescent staining protocols; 5-carboxyfluorescein-labeled octreotate was synthesized for targeted molecular imaging. RESULTS: Cellular and subcellular details of the gastrointestinal tract could be visualized in vivo at high resolution. Confocal real-time microscopy allowed in-vivo identification of tumor vessels and liver metastases, as well as diagnosis of focal hepatic inflammation, necrosis, and associated perfusion anomalies. Somatostatin-receptor targeting permitted in-vivo molecular staining of AR42-J-induced carcinoma and pancreatic islet cells. CONCLUSIONS: Confocal mini-microscopy allows rapid in-vivo molecular and subsurface imaging of normal and pathological tissue in the gastrointestinal tract at high resolution. Because this technology is applicable to humans, it might impact on future in-vivo microsocpic and molecular diagnosis of diseases such as cancer and inflammation.

Demonstration of pulmonary beta2-adrenergic receptor binding in vivo with [18F]fluoroethyl-fenoterol in a guinea pig model.

PURPOSE: The new beta2 radioligand (R,R)(S,S) 5-(2-(2-[4-(2-[18F]fluoroethoxy)phenyl]-1-methylethylamino)-1-hydroxyethyl)-benzene-1,3-diol ([18F]FE-fenoterol; [18F]FEFE), a fluoroethylated derivative of racemic fenoterol, was evaluated in vivo and ex vivo using a guinea pig model. METHODS: Dynamic PET studies over 60 min with [(18)F]FEFE were performed in nine Hartley guinea pigs in which a baseline (group 1, n=3), a predose (group 2, n=3; 2 mg/kg fenoterol 5 min prior to injection of [18F]FEFE) or a displacement study (group 3, n=3; 2 mg/kg fenoterol 5 min post injection of [18F]FEFE) was conducted. RESULTS: In all animal groups, the lungs could be visualised and semi-quantified separately by calculating uptake ratios to non-specific binding in the neck area. Premedication with non-radioactive fenoterol and displacement tests showed significant reduction of lung uptake, by 94% and 76%, respectively. CONCLUSION: These data demonstrate specific binding of the new radioligand to the pulmonary beta2-receptors in accordance with ex vivo measurements. Therefore, [18F]FEFE seems to be suitable for the in vivo visualisation and quantification of the pulmonary beta2-receptor binding in this animal model.

In vitro and in vivo evaluation of novel glibenclamide derivatives as imaging agents for the non-invasive assessment of the pancreatic islet cell mass in animals and humans.

Pancreatic islet cell mass (PICM) is a major determinant of the insulin secretory capacity in humans. Currently, the only method for accurate assessment of the PICM is an autopsy study. Thus, development of a technique allowing the non-invasive quantification of PICM is of great interest. The aim of this study was to develop such a non-invasive technique featuring novel fluorine- and (99m)Tc-labelled glibenclamide derivatives. Despite the structural modifications necessary to introduce fluorine into the glibenclamide molecule, all derivatives retained insulin stimulating capacity as well as high affinity binding to human SUR1 when compared to the original glibenclamide. Contrastingly, the lipophilicity of the fluorine-labelled derivatives was altered depending on the particular modification. In the human PET-study a constant but weak radioactive signal could be detected in the pancreas using a fluorine-labelled glibenclamide derivative. However, a reliable assessment and visualisation of the PICM could not be obtained. It can be assumed that the high uptake of the fluorine-labelled tracer e.g. into the the liver and the high plasma protein binding leads to a relatively low signal-to-noise ratio. In case of the presented fluorine-labelled glibenclamide based compounds this could be the result of their invariably high lipophilicity. The development of a (99 m)Tc-labelled glibenclamide derivative with a lower lipophilicity and differing in vivo behaviour, glibenclamide based compounds for non-invasive imaging of the pancreatic islet cell mass may be possible.

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 beta-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 was in the range of 50-60 GBq/micromol. Labeling was conducted by exchanging the ethoxy-moiety into a 2-[(18)F]fluoroethoxy group. To characterize the properties of fluorinated repaglinide, the affinity of the analogous non-radioactive (19)F-compound for binding to the human SUR1 isoform was assessed. [(19)F]Repaglinide induced a complete monophasic inhibition curve with a Hill coefficient close to 1 (1.03) yielding a dissociation constant (K(D)) of 134 nM. Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide. Finally, biodistribution of [(18)F]repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i.v. injection. Pancreatic tissue displayed a stable accumulation of approximately 0.12% of the injected dose from 10 min to 30 min p.i. 50% of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide, indicating that [(18)F]repaglinide might be suitable for in vivo investigation with PET.

Synthesis and evaluation of fluorine-18 labeled glyburide analogs as beta-cell imaging agents.

Glyburide is a prescribed hypoglycemic drug for the treatment of type 2 diabetic patients. We have synthesized two of its analogs, namely N-[4-[beta-(2-(2'-fluoroethoxy)-5-chlorobenzenecarboxamido)ethyl]benzenesulfonyl]-N'-cyclohexylurea (2-fluoroethoxyglyburide, 8b) and N-[4-[beta-(2-(2'-fluoroethoxy)-5-iodobenzenecarboxamido)ethyl]benzenesulfonyl]-N'-cyclohexylurea (2-fluoroethoxy-5-deschloro-5-iodoglyburide, 8a), and their fluorine-18 labeled analogs as beta-cell imaging agents. Both F-18 labeled compound 8a and compound 8b were synthesized by alkylation of the corresponding multistep synthesized hydroxy precursor 4a and 4b with 2-[(18)F]fluoroethyl tosylate in DMSO at 120 degrees C for 20 minutes followed by HPLC purification in an overall radiochemical yield of 5-10% with a synthesis time of 100 minutes from EOB. The octanol/water partition coefficients of compounds 8a and 8b were 141.21 +/- 27.77 (n = 8) and 124.33 +/- 21.61 (n = 8), respectively. Insulin secretion experiments of compounds 8a and 8b on rat islets showed that both compounds have a similar stimulating effect on insulin secretion as that of glyburide. In vitro binding studies showed that approximately 2% of compounds 8a and 8b bound to beta TC3 and Min6 cells and that the binding was saturable. Preliminary biodistribution studies in mice showed that the uptake of both compounds 8a and 8b in liver and small intestine were high, whereas the uptake in other organs studied including pancreas were low. Additionally, the uptake of compound 8b in vivo was nonsaturable. These results tend to suggest that compounds 8a and 8b may not be the ideal beta-cell imaging agents.

Efficient synthesis of 2-bromo-1-[18F]fluoroethane and its application in the automated preparation of 18F-fluoroethylated compounds.

An efficient synthesis of 2-bromo-1-[18F]fluoroethane from commercially available 1,2-dibromoethane and its integration into an automated preparation device was developed for the routine synthesis of 18F-fluoroethylated compounds. The 1,2-dibromoethane was reacted with the [18F]fluoride/Kryptofix 2.2.2./carbonate complex in acetonitrile at 70 degrees C for 3 min resulting in 60-70% radiochemical yields. The crude reaction mixture was diluted with water, loaded on a LiChrolute EN-cartridge, eluted with acetonitrile and passed through an AluminaB-cartridge. This method provides 2-bromo-1-[18F]fluoroethane with 98% radiochemical purity and <0.1 micromol of 1,2-dibromoethane within 10 min, thus avoiding a purifying distillation step. This method was easily integrated into an automated system for the routine synthesis of 18F-fluoroethylated compounds.