18F-labelled triazolyl-linked argininamides targeting the neuropeptide Y Y1R for PET Imaging of mammary carcinoma

NeuropeptideYY(1) receptors (Y1R) have been found to be overexpressed in a number of different tumours, such as breast, ovarian or renal cell cancer. In mammary carcinoma the highY(1)R density together with its high incidence of 85% in primary human breast cancers and 100% in breast cancer derived lymph node metastases attracted special attention. Therefore, the aim of this study was the development of radioligandsforY(1)R imaging by positron emission tomography (PET) with a special emphasis on imaging agents with reduced lipophilicity to provide a PET ligand with improved biodistribution in comparison with previously published tracers targeting theY(1)R. Three new radioligands based on BIBP3226, bearing an F-18-fluoroethoxy linker (12), an F-18-PEG-linker (13) or an F-18-fluoroglycosyl moiety (11) were radiosynthesised in high radioactivity yields. The new radioligands displayedY(1)R affinities of 2.8 nM (12), 29 nM (13) and 208 nM (11) and were characterised in vitro regarding binding to human breast cancer MCF-7-Y1 cells and slices of tumour xenografts. In vivo, small animal PET studies were conducted in nude mice bearing MCF-7-Y1 tumours. The binding to tumours, solid tumour slices and tumour cells correlated well with theY(1)R affinities. Although 12 and 13 showed displaceable and specific binding toY(1)R in vitro and in vivo, the radioligands still need to be optimised to achieve higher tumour-to-background ratios forY(1)R imaging by PET.Yet the present study is another step towards an optimized PET radioligand for imaging ofY(1)R in vivo

F-labeled glycoconjugate of PD156707 for imaging ET A receptor expression in thyroid carcinoma by positron emission tomography

Abstract: Disturbances of the endothelin axis have been described in tumor angiogenesis and in highly vascularized tumors, such as thyroid carcinoma. Consequently, the endothelin (ET) receptor offers a molecular target for the visualization of the endothelin system in vivo by positron emission tomography (PET). We therefore endeavoured to develop a subtype-selective ET A receptor (ET A R) radioligand by introduction of a glycosyl moiety as a hydrophilic building block into the lead compound PD156707. Employing click chemistry we synthesized the triazolyl conjugated fluoroglucosyl derivative 1 that had high selectivity for ET A R (4.5 nM) over ET B R (1.2 µM)

N-glycosylation regulates intrinsic IFN-γ resistance in colorectal cancer: implications for immunotherapy

Background & Aims: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored. Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines. Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling. Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC

Sweetening Pharmaceutical Radiochemistry by 18F-Fluoroglycosylation: A Short Review

At the time when the highly efficient [18F]FDG synthesis was discovered by the use of the effective precursor 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranose (mannose triflate) for nucleophilic 18F-substitution, the field of PET in nuclear medicine experienced a long-term boom. Thirty years later, various strategies for chemoselective 18F-labeling of biomolecules have been developed, trying to keep up with the emerging field of radiopharmaceutical sciences. Among the new radiochemical strategies, chemoselective 18F-fluoroglycosylation methods aim at the sweetening of pharmaceutical radiochemistry by providing a powerful and highly valuable tool for the design of 18F-glycoconjugates with suitable in vivo properties for PET imaging studies. This paper provides a short review (reflecting the literature not older than 8 years) on the different 18F-fluoroglycosylation reactions that have been applied to the development of various 18F-glycoconjugate tracers, including not only peptides, but also nonpeptidic tracers and high-molecular-weight proteins

Sweetening Pharmaceutical Radiochemistry by 18F-Fluoroglycosylation: A Short Review

At the time when the highly efficient [18F]FDG synthesis was discovered by the use of the effective precursor 1,3,4,6-tetra-O-acetyl-2-O-trifluoromethanesulfonyl-β-D-mannopyranose (mannose triflate) for nucleophilic 18F-substitution, the field of PET in nuclear medicine experienced a long-term boom. Thirty years later, various strategies for chemoselective 18F-labeling of biomolecules have been developed, trying to keep up with the emerging field of radiopharmaceutical sciences. Among the new radiochemical strategies, chemoselective 18F-fluoroglycosylation methods aim at the sweetening of pharmaceutical radiochemistry by providing a powerful and highly valuable tool for the design of 18F-glycoconjugates with suitable in vivo properties for PET imaging studies. This paper provides a short review (reflecting the literature not older than 8 years) on the different 18F-fluoroglycosylation reactions that have been applied to the development of various 18F-glycoconjugate tracers, including not only peptides, but also nonpeptidic tracers and high-molecular-weight proteins

Sweetening Pharmaceutical Radiochemistry by 18F-Fluoroglycosylation: Recent Progress and Future Prospects

In the field of 18F-chemistry for the development of radiopharmaceuticals for positron emission tomography (PET), various labeling strategies by the use of prosthetic groups have been implemented, including chemoselective 18F-labeling of biomolecules. Among those, chemoselective 18F-fluoroglycosylation methods focus on the sweetening of pharmaceutical radiochemistry by offering a highly valuable tool for the synthesis of 18F-glycoconjugates with suitable in vivo properties for PET imaging studies. A previous review covered the various 18F-fluoroglycosylation methods that were developed and applied as of 2014 (Maschauer and Prante, BioMed. Res. Int. 2014, 214748). This paper is an updated review, providing the recent progress in 18F-fluoroglycosylation reactions and the preclinical application of 18F-glycoconjugates, including small molecules, peptides, and high-molecular-weight proteins

PET Radiopharmaceuticals for Imaging Integrin Expression: Tracers in Clinical Studies and Recent Developments

Noninvasive determination of integrin expression has become an interesting approach in nuclear medicine. Since the discovery of the first 18F-labeled cyclic RGD peptide as radiotracer for imaging integrin expression in vivo, there have been carried out enormous efforts to develop RGD peptides for PET imaging. Moreover, in recent years, additional integrins, including and , came into the focus of pharmaceutical radiochemistry. This review will discuss the tracers already evaluated in clinical trials and summarize the preliminary outcome. It will also give an overview on recent developments to further optimize the first-generation compounds such as [18F]Galacto-RGD. This includes recently developed 18F-labeling strategies and also new approaches in 68Ga-complex chemistry. Furthermore, the approaches to develop radiopharmaceuticals targeting integrin and will be summarized and discussed

Detection of monoamine oxidase a in brain of living rats with [18F]fluoroethyl-harmol PET

Monoamine oxidase A (MAO-A) in brain, sympathetic fibres, and neuroendocrine tissues can catalyze the oxidative deamination of serotonin, noradrenaline and adrenaline, and contributes, along with MAO-B,to the catabolism of brain dopamine. As such, MAO-A is potentially an important target for molecular imaging, although the repertoire of suitable radiotracers is rather limited. The first successful MAO-A ligand for positron emission tomography (PET) studies of\ud MAO-A was the b-carboline [11 C]harmine, which binds reversibly with nM affinity and high selectivity to the enzyme (Bergstrom et al., 1997). In contrast,\ud the cerebral binding to MAO-A of [11C]clorgyline is difficult to quantify since the rate constant for irreversible binding is so very high, and due to the presence of a nonspecific binding component in white\ud matter (Fowler et al., 2001). Other reversibly binding\ud PET ligands for MAO-A include [11 C]befloxatone (Zanotti-Fregonara et al., 2013) and [11 C]ROMAO (Jensen et al., 2008). However, only [11 C]harmine is currently finding use in human PET studies of brain MAO-A (Chiuccariello et al., 2014). Logistic issues arising from the brief half-life of carbon-11 may be limiting the wider use of [11 C]harmine and other MAO-A ligands in research. Obtaining an MAO-A\ud ligand labelled with fluorine-18 might afford multiple\ud scans from a single radiosynthesis, and would make\ud MAO-A scanning available to research centers lacking\ud a medical cyclotron. In two preliminary reports, the b-\ud carboline [18 F]fluoroethyl-harmol was found to have\ud good properties for imaging in vivo, including high\ud affinity and specificity, while corresponding PEGylated\ud derivatives did not cross the blood-brain-barrier (Blom\ud et al., 2008; Schieferstein et al., 2012). However, the\ud specific binding of [18 F]fluoroethyl-harmol was not\ud reported in detail in those reports. In this study, we\ud report a high yield radiosynthesis of [18 F]fluoroethyl-\ud harmol, and use small animal PET to map the distribution of its specific binding in brain of living rat

In Vitro and In Vivo Characterization of Selected Fluorine-18 Labeled Radioligands for PET Imaging of the Dopamine D3 Receptor

Cerebral dopamine D3 receptors seem to play a key role in the control of drug-seeking behavior. The imaging of their regional density with positron emission tomography (PET) could thus help in the exploration of the molecular basis of drug addiction. A fluorine-18 labeled D3 subtype selective radioligand would be beneficial for this purpose; however, as yet, there is no such tracer available. The three candidates [18F]1, [18F]2a and [18F]2b were chosen for in vitro and in vivo characterization as radioligands suitable for selective PET imaging of the D3 receptor. Their evaluation included the analysis of radiometabolites and the assessment of non-specific binding by in vitro rat brain autoradiography. While [18F]1 and [18F]2a revealed high non-specific uptake in in vitro rat brain autoradiography, the D3 receptor density was successfully determined on rat brain sections (n = 4) with the candidate [18F]2b offering a Bmax of 20.38 ± 2.67 pmol/g for the islands of Calleja, 19.54 ± 1.85 pmol/g for the nucleus accumbens and 16.58 ± 1.63 pmol/g for the caudate putamen. In PET imaging studies, the carboxamide 1 revealed low signal/background ratios in the rat brain and relatively low uptake in the pituitary gland, while the azocarboxamides [18F]2a and [18F]2b showed binding that was blockable by the D3 receptor ligand BP897 in the ventricular system and the pituitary gland in PET imaging studies in living rats

Biodistribution studies of two 18F-labeled pyridinylphenyl amides as subtype selective radioligands for the dopamine D3 receptor

Introduction Dopamine D3 receptors are implicated in various neuropsychiatric diseases, drug abuse and alcoholism, but specific agents for D3 molecular imaging are lacking. We evaluated two in vitro selective fluorine-18-labeled radioligand candidates ([18F]5 and [18F]6) for positron emission tomography (PET) imaging of D3 receptor availability in the brain.MethodsBiodistribution was evaluated in Sprague–Dawley rats using ex vivo autoradiography and small-animal PET. Protein binding studies were conducted in human plasma and cerebrospinal fluid.Results[18F]5 showed rapid blood–brain barrier penetration and fast washout after intravenous injection, whereas the rat brain penetration of [18F]6 was lower. The total distribution volume (VT) of [18F]5 was 20–26 mL g− 1 throughout brain. Co-injection with the D3 antagonist BP897 resulted in globally increased cerebral washout of [18F]5 and [18F]6, but SUV analysis and parametric mapping of binding potential (BPND) relative to the cerebellum did not reveal specific binding of either ligand in D3-rich brain regions, i.e. the ventral striatum. However, there was substantial displaceable binding of [18F]5, and to a lesser extent [18F]6, in the pituitary.ConclusionThese radioligands reveal dopamine D3 receptors in the pituitary, but are not suitable for PET imaging of in brain, possibly due to low specific signal relative to the globally high VT</sub