Dataset Information

Synthesis and characterization of a novel 18F-labeled 2,5-diarylnicotinamide derivative targeting orexin 2 receptor.

ABSTRACT: Orexin 2 receptor (OX2R) is thought to play an important role in the arousal-promoting function, but its distribution and function in the pathophysiology of orexin-mediated disorders remains to be fully elucidated. In the present study, we synthesized and characterized a novel 18F-labeled 2,5-diarylnicotinamide (DAN) derivative as a potential positron emission tomography (PET) probe for in vivo imaging of OX2R. In in vitro binding experiments, [18F]DAN-1 selectively bound to OX2R. In a biodistribution study using normal mice, [18F]DAN-1 displayed moderate brain uptake (2.10% ID per g at 10 min post-injection). In addition, the radioactivity in the mouse brain at 30 min post-injection was significantly decreased by co-injection with nonradioactive DAN-1, but high nonspecific binding was observed. These results suggested that further structural modifications of [18F]DAN-1 are needed to use it for imaging OX2R in the brain.

SUBMITTER: Watanabe H

PROVIDER: S-EPMC7451066 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synthesis and characterization of a novel 18F-labeled 2,5-diarylnicotinamide derivative targeting orexin 2 receptor.

Watanabe Hiroyuki H Matsushita Naoki N Shimizu Yoichi Y Iikuni Shimpei S Nakamoto Yuji Y Togashi Kaori K Ono Masahiro M

MedChemComm 20191118 12

Orexin 2 receptor (OX2R) is thought to play an important role in the arousal-promoting function, but its distribution and function in the pathophysiology of orexin-mediated disorders remains to be fully elucidated. In the present study, we synthesized and characterized a novel 18F-labeled 2,5-diarylnicotinamide (DAN) derivative as a potential positron emission tomography (PET) probe for in vivo imaging of OX2R. In in vitro binding experiments, [<sup ...[more]

PMID: 32904113

Similar Datasets

Project description:PurposeMetabotropic glutamate receptor 2 (mGluR2) has been implicated in various psychiatric and neurological disorders, such as schizophrenia and Alzheimer's disease. We have previously developed [11C]7 as a PET radioligand for imaging mGluR2. Herein, [18F]JNJ-46356479 ([18F]8) was synthesized and characterized as the first 18F-labeled mGluR2 imaging ligand to enhance diagnostic approaches for mGluR2-related disorders.ProceduresJNJ-46356479 (8) was radiolabeled via the copper (I)-mediated radiofluorination of organoborane 9. In vivo PET imaging experiments with [18F]8 were conducted first in C57BL/6 J mice and Sprague-Dawley rats to obtain whole body biodistribution and brain uptake profile. Subsequent PET studies were done in a cynomolgus monkey (Macaca fascicularis) to investigate the uptake of [18F]8 in the brain, its metabolic stability, as well as pharmacokinetic properties.ResultsJNJ-46356479 (8) exhibited excellent selectivity against other mGluRs. In vivo PET imaging studies showed reversible and specific binding characteristic of [18F]8 in rodents. In the non-human primate, [18F]8 displayed good in vivo metabolic stability, excellent brain permeability, fast and reversible kinetics with moderate heterogeneity across brain regions. Pre-treatment studies with compound 7 revealed time-dependent decrease of [18F]8 accumulation in mGluR2 rich regions based on SUV values with the highest decrease in the nucleus accumbens (18.7 ± 5.9%) followed by the cerebellum (18.0 ± 7.9%), the parietal cortex (16.9 ± 7.8%), and the hippocampus (16.8 ± 6.9%), similar to results obtained in the rat studies. However, the volume of distribution (VT) results derived from 2T4k model showed enhanced VT from a blocking study with compound 7. This is probably because of the potentiating effect of compound 7 as an mGluR2 PAM as well as related non-specific binding in the tissue data.Conclusions[18F]8 readily crosses the blood-brain barrier and demonstrates fast and reversible kinetics both in rodents and in a non-human primate. Further investigation of [18F]8 on its binding specificity would warrant translational study in human.

Project description:BackgroundCancer-associated fibroblasts are found in the stroma of epithelial tumors. They are characterized by overexpression of the fibroblast activation protein (FAP), a serine protease which was already proven as attractive target for chelator-based theranostics. Unfortunately, the value of gallium-68 labeled tracers is limited by their batch size and the short nuclide half-life. To overcome this drawback, radiolabeling with aluminum fluoride complexes and 6-fluoronicotinamide derivatives of the longer-lived nuclide fluorine-18 was established. The novel compounds were tested for their FAP-specific binding affinity. Uptake and binding competition were studied in vitro using FAP expressing HT-1080 cells. HEK cells transfected with the closely related dipeptidyl peptidase-4 (HEK-CD26) were used as negative control. Small animal positron emission tomography imaging and biodistribution experiments were performed in HT-1080-FAP xenografted nude mice. [18F]AlF-FAPI-74 was selected for PET/CT imaging in a non-small cell lung cancer (NSCLC) patient.ResultsIn vitro, 18F-labeled FAPI-derivatives demonstrated high affinity (EC50 = < 1 nm to 4.2 nm) and binding of up to 80% to the FAP-expressing HT1080 cells while no binding to HEK-CD26 cells was observed. While small animal PET imaging revealed unfavorable biliary excretion of most of the 18F-labeled compounds, the NOTA bearing compounds [18F]AlF-FAPI-74 and -75 achieved good tumor-to-background ratios, as a result of their preferred renal excretion. These two compounds showed the highest tumor accumulation in PET imaging. The organ distribution values of [18F]AlF-FAPI-74 were in accordance with the small animal PET imaging results. Due to its less complex synthesis, fast clearance and low background values, [18F]AlF-FAPI-74 was chosen for clinical imaging. PET/CT of a patient with metastasized non-small cell lung cancer (NSCLC), enabled visualization of the primary tumor and its metastases at the hepatic portal and in several bones. This was accompanied by a rapid clearance from the blood pool and low background in healthy organs.Conclusion[18F]AlF-labeled FAPI derivatives represent powerful tracers for PET. Owing to an excellent performance in PET imaging, FAPI-74 can be regarded as a promising precursor for [18F]AlF-based FAP-imaging.

Dataset Information

Synthesis and characterization of a novel 18F-labeled 2,5-diarylnicotinamide derivative targeting orexin 2 receptor.

Publications

Synthesis and characterization of a novel <sup>18</sup>F-labeled 2,5-diarylnicotinamide derivative targeting orexin 2 receptor.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets