N-(4-[18F]fluorobenzyl)cholylglycine, a novel tracer for PET of enterohepatic circulation of bile acids: radiosynthesis and proof-of-concept studies in rats

Enterohepatic circulation (EHC) of conjugated bile acids is an important physiological process crucial for regulation of intracellular concentrations of bile acids and their function as detergents and signal carriers. Only few bile acid-derived imaging agents have been synthesized and hitherto none have been evaluated for studies of EHC. We hypothesized that N-(4-[F]fluorobenzyl)cholylglycine ([F]FBCGly), a novel fluorine-18 labeled derivative of endogenous cholylglycine, would be a suitable tracer for PET of the EHC of conjugated bile acids, and we report here a radiosynthesis of [F]FBCGly and a proof-of-concept study by PET/MR in rats.A radiosynthesis of [F]FBCGly was developed based on reductive alkylation of glycine with 4-[F]fluorobenzaldehyde followed by coupling to cholic acid. [F]FBCGly was investigated in vivo by dynamic PET/MR in anesthetized rats; untreated or treated with cholyltaurine or rifampicin. Possible in vivo metabolites of [F]FBCGly were investigated by analysis of blood and bile samples, and the stability of [F]FBCGly towards enzymatic de-conjugation by Cholylglycine Hydrolase was tested in vitro.[F]FBCGly was produced with a radiochemical purity of 96% ± 1% and a non-decay corrected radiochemical yield of 1.0% ± 0.3% (mean ± SD; n = 12). PET/MR studies showed that i.v.-administrated [F]FBCGly underwent EHC within 40-60 min with a rapid transhepatic transport from blood to bile. In untreated rats, the radioactivity concentration of [F]FBCGly was approximately 15 times higher in bile than in liver tissue. Cholyltaurine and rifampicin inhibited the biliary secretion of [F]FBCGly. No fluorine-18 metabolites of [F]FBCGly were observed.We have developed a radiosynthesis of a novel fluorine-18 labeled bile acid derivative, [F]FBCGly, and shown by PET/MR that [F]FBCGly undergoes continuous EHC in rats without metabolizing. This novel tracer may prove useful in PET studies on the effect of drugs or diseases on the EHC of conjugated bile acids

Synthesis and characterisation of indium(iii) bis-thiosemicarbazone complexes: 18 F incorporation for PET imaging

Several structurally related indium chlorido complexes of bis-thiosemicarbazones were prepared, starting from the appropriately substituted bis-thiosemicarbazones, using sodium methoxide in methanol. Detailed NMR studies were conducted to assign the structure including COSY, HSQC, and HMBC techniques. The structures of all indium complexes were solved using single crystal X-ray diffraction. The chlorido ligand was present at the apex of the square pyramidal coordination sphere in all indium complexes. In some complexes, an intermolecular hydrogen bond was present between the chlorine atom and an NH group. Three different indium chlorido complexes were converted into the corresponding fluorido-derivative by a simple halide exchange method using K F. These novel complexes, containing the positron emitting isotope F, may have potential applications in positron emission tomography (PET)

Synthesis and: In vitro evaluation of fluorine-18 benzimidazole sulfones as CB2 PET-radioligands

Cannabinoid type 2 receptor (CB2) is up-regulated on activated microglial cells and can potentially be used as a biomarker for PET-imaging of neuroinflammation. In this study the synthesis and pharmacological evaluation of novel fluorinated pyridyl and ethyl sulfone analogues of 2-(tert-butyl)-5-((2-fluoropyridin-4-yl)sulfonyl)-1-(2-methylpentyl)-1H-benzo[d]imidazole (rac-1a) are described. In general, the ligands showed low nanomolar potency (CB2 EC 10 000×). Selected ligands 1d, 1e, 1g and 3l showing high CB2 binding affinity (K < 10 nM) were radiolabelled with fluorine-18 from chloropyridyl and alkyl tosylate precursors with good to high isolated radioactive yields (25-44%, non-decay corrected, at the end of synthesis). CB2-specific binding of the radioligand candidates [F]-1d and [F]-3l was assessed on rat spleen cryosections using in vitro autoradiography. The results warrant further in vivo evaluation of the tracer candidates as prospective CB2 PET-imaging agents

A binge high sucrose diet provokes systemic and cerebral inflammation in rats without inducing obesity.

While the dire cardiometabolic consequences of the hypercaloric modern 'Western' diet are well known, there is not much information on the health impact of a high sucrose diet not inducing weight gain. Here, we tested the hypothesis that rats reared with intermittent binge access to sucrose in addition to normal chow would develop an inflammatory response in brain. To test this hypothesis, we undertook serial PET/MRI scans with the TSPO ligand [18F]DPA714 in a group of (n=9) rats at baseline and again after voluntarily consuming 5% sucrose solution three days a week for three months. Compared to a control group fed with normal chow (n=9), the sucrose rats indeed showed widespread increases in the availability of cerebral binding sites for the microglial marker, despite normal weight gain compared to the control diet group. Subsequent immunofluorescence staining of the brains confirmed the PET findings, showing a widespread 20% increase in the abundance of IBA-1-positive microglia with characteristic 'semi-activated' morphology in the binge sucrose rats, which had 23% lower density of microglial endpoints and 25% lower mean process length compared to microglia in the control rats with ordinary feeding. GFAP immunofluorescence showed no difference in astroglial coverage in the sucrose rats, except for a slight reduction in hypothalamus. The binge sucrose diet-induced neuroinflammation was associated with a significant elevation of white blood cell counts. Taking these results together, we find that long-term intake of sucrose in a binge paradigm, similar in sucrose content to the contemporary Western diet, triggered a low-grade systemic and central inflammation in non-obese rats. The molecular mechanism of this phenomenon remains to be established

Utilizing PET and MALDI Imaging for Discovery of a Targeted Probe for Brain Endocannabinoid α/β-Hydrolase Domain 6 (ABHD6)

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