Dataset Information

Synthesis and Screening in Mice of Fluorine-Containing PET Radioligands for TSPO: Discovery of a Promising ¹⁸F-Labeled Ligand.

ABSTRACT: Translocator protein 18 kDa (TSPO) is a biomarker of neuroinflammation. [¹¹C]ER176 robustly quantifies TSPO in the human brain with positron emission tomography (PET), irrespective of subject genotype. We aimed to develop an ER176 analog with potential for labeling with longer-lived fluorine-18 (t_1/2 = 109.8 min). New fluoro and trifluoromethyl analogs of ER176 were prepared through a concise synthetic strategy. These ligands showed high TSPO affinity and low human genotype sensitivity. Each ligand was initially labeled by a generic ¹¹C-methylation procedure, thereby enabling speedy screening in mice. Each radioligand was rapidly taken up and well retained in the mouse brain at baseline after intravenous injection. Preblocking of TSPO showed that high proportions of brain uptake were specifically bound to TSPO at baseline. Overall, the 3-fluoro analog of [¹¹C]ER176 ([¹¹C]3b) displayed the most promising imaging properties. Therefore, a method was developed to label 3b with [¹⁸F]fluoride ion. [¹⁸F]3b gave similarly promising PET imaging results and deserves evaluation in higher species.

SUBMITTER: Simeon FG

PROVIDER: S-EPMC8817670 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Synthesis and Screening in Mice of Fluorine-Containing PET Radioligands for TSPO: Discovery of a Promising 18F-Labeled Ligand.

Siméon Fabrice G FG Lee Jae-Hoon JH Morse Cheryl L CL Stukes Ian I Zoghbi Sami S SS Manly Lester S LS Liow Jeih-San JS Gladding Robert L RL Dick Rachel M RM Yan Xuefeng X Taliani Sabrina S Costa Barbara B Martini Claudia C Da Settimo Federico F Castellano Sabrina S Innis Robert B RB Pike Victor W VW

Journal of medicinal chemistry 20211110 22

Translocator protein 18 kDa (TSPO) is a biomarker of neuroinflammation. [11C]ER176 robustly quantifies TSPO in the human brain with positron emission tomography (PET), irrespective of subject genotype. We aimed to develop an ER176 analog with potential for labeling with longer-lived fluorine-18 (t1/2 = 109.8 min). New fluoro and trifluoromethyl analogs of ER176 were prepared through a concise synthetic strategy. These ligands showed high TSPO affinity and low human g ...[more]

PMID: 34756026

Similar Datasets

Project description:Purpose[18F]SF51 was previously found to have high binding affinity and selectivity for 18 kDa translocator protein (TSPO) in mouse brain. This study sought to assess the ability of [18F]SF51 to quantify TSPO in rhesus monkey brain.MethodsPositron emission tomography (PET) imaging was performed in monkey brain (n = 3) at baseline and after pre-blockade with the TSPO ligands PK11195 and PBR28. TSPO binding was calculated as total distribution volume corrected for free parent fraction in plasma (VT/fP) using a two-tissue compartment model. Receptor occupancy and nondisplaceable uptake were determined via Lassen plot. Binding potential (BPND) was calculated as the ratio of specific binding to nondisplaceable uptake. Time stability of VT was used as an indirect probe to detect radiometabolite accumulation in the brain. In vivo and ex vivo experiments were performed in mice to determine the distribution of the radioligand.ResultsAfter [18F]SF51 injection, the concentration of brain radioactivity peaked at 2.0 standardized uptake value (SUV) at ~ 10 min and declined to 30% of the peak at 180 min. VT/fP at baseline was generally high (203 ± 15 mL· cm-3) and decreased by ~ 90% after blockade with PK11195. BPND of the whole brain was 7.6 ± 4.3. VT values reached levels similar to terminal 180-min values by 100 min and remained relatively stable thereafter with excellent identifiability (standard errors < 5%), suggesting that no significant radiometabolites accumulated in the brain. Ex vivo experiments in mouse brain showed that 96% of radioactivity was parent. No significant uptake was observed in the skull, suggesting a lack of defluorination in vivo.ConclusionThe results demonstrate that [18F]SF51 is an excellent radioligand that can quantify TSPO with a good ratio of specific to nondisplaceable uptake and has minimal radiometabolite accumulation in brain. Collectively, the results suggest that [18F]SF51 warrants further evaluation in humans.

Project description:PurposeTranslocator protein 18-kDa (TSPO) positron emission tomography (PET) is a valuable tool to detect neuroinflammed areas in a broad spectrum of neurodegenerative diseases. However, the clinical application of second-generation TSPO ligands as biomarkers is limited because of the presence of human rs6971 polymorphism that affects their binding. Here, we describe the ability of a new TSPO ligand, [18F]BS224, to identify abnormal TSPO expression in neuroinflammation independent of the rs6971 polymorphism.MethodsAn in vitro competitive inhibition assay of BS224 was conducted with [3H]PK 11195 using membrane proteins isolated from 293FT cells expressing TSPO-wild type (WT) or TSPO-mutant A147T (Mut), corresponding to a high-affinity binder (HAB) and low-affinity binder (LAB), respectively. Molecular docking was performed to investigate the interaction of BS224 with the binding sites of rat TSPO-WT and TSPO-Mut. We synthesized a new 18F-labeled imidazopyridine acetamide ([18F]BS224) using boronic acid pinacol ester 6 or iodotoluene tosylate precursor 7, respectively, via aromatic 18F-fluorination. Dynamic PET scanning was performed up to 90 min after the injection of [18F]BS224 to healthy mice, and PET imaging data were obtained to estimate its absorbed doses in organs. To evaluate in vivo TSPO-specific uptake of [18F]BS224, lipopolysaccharide (LPS)-induced inflammatory and ischemic stroke rat models were used.ResultsBS224 exhibited a high affinity (Ki = 0.51 nM) and selectivity for TSPO. The ratio of IC50 values of BS224 for LAB to that for HAB indicated that the TSPO binding affinity of BS224 has low binding sensitivity to the rs6971 polymorphism and it was comparable to that of PK 11195, which is not sensitive to the polymorphism. Docking simulations showed that the binding mode of BS224 is not affected by the A147T mutation and consequently supported the observed in vitro selectivity of [18F]BS224 regardless of polymorphisms. With optimal radiochemical yield (39 ± 6.8%, decay-corrected) and purity (> 99%), [18F]BS224 provided a clear visible image of the inflammatory lesion with a high signal-to-background ratio in both animal models (BPND = 1.43 ± 0.17 and 1.57 ± 0.37 in the LPS-induced inflammatory and ischemic stroke rat models, respectively) without skull uptake.ConclusionOur results suggest that [18F]BS224 may be a promising TSPO ligand to gauge neuroinflammatory disease-related areas in a broad range of patients irrespective of the common rs6971 polymorphism.

Project description:PurposeWhile the aetiology of rheumatoid arthritis (RA) remains unclear, many of the inflammatory components are well characterised. For diagnosis and therapy evaluation, in vivo insight into these processes would be valuable. Various imaging probes have shown value including dynamic contrast-enhanced (DCE) MRI and PET/CT using 18F-fluorodeoxyglucose (18F-FDG) or tracers targeting the translocator protein (TSPO). To evaluate 18F-GE-180, a novel TSPO PET tracer, for detecting and quantifying disease activity in RA, we compared 18F-GE-180 uptake with that of 18F-FDG and DCE-MRI measures of inflammation.MethodsEight RA patients with moderate-to-high, stable disease activity and active disease in at least one wrist were included in this study (NCT02350426). Participants underwent PET/CT examinations with 18F-GE-180 and 18F-FDG on separate visits, covering the shoulders and from the pelvis to the feet, including hands and wrists. DCE-MRI was performed on one affected hand. Uptake was compared visually between tracers as judged by an experienced radiologist and quantitatively using the maximum standardised uptake value (SUVmax). Uptake for both tracers was correlated with DCE-MRI parameters of inflammation, including the volume transfer coefficient Ktrans using Pearson correlation (r).ResultsPET/CT imaging with 18F-GE-180 in RA patients showed marked extra-synovial uptake around the affected joints. Overall sensitivity for detecting clinically affected joints was low (14%). 18F-GE-180 uptake did not or only weakly correlate with DCE-MRI parameters in the wrist (r = 0.09-0.31). 18F-FDG showed higher sensitivity for detecting symptomatic joints (34%), as well as strong positive correlation with DCE-MRI parameters (SUVmax vs. Ktrans: r = 0.92 for wrist; r = 0.68 for metacarpophalangeal joints).ConclusionsThe correlations between DCE-MRI parameters and 18F-FDG uptake support use of this PET tracer for quantification of inflammatory burden in RA. The TSPO tracer 18F-GE-180, however, has shown limited use for the investigation of RA due to its poor sensitivity and ability to quantify disease activity in RA.

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:PurposePositron emission tomography (PET) ligands targeting translocator protein (TSPO) are potential imaging diagnostics of cancer. In this study, we report two novel, high-affinity TSPO PET ligands that are 5,7 regioisomers, [18F]VUIIS1009A ([18F]3A) and [18F]VUIIS1009B ([18F]3B), and their initial in vitro and in vivo evaluation in healthy mice and glioma-bearing rats.ProceduresVUIIS1009A/B was synthesized and confirmed by X-ray crystallography. Interactions between TSPO binding pocket and novel ligands were evaluated and compared with contemporary TSPO ligands using 2D 1H-15N heteronuclear single quantum coherence (HSQC) spectroscopy. In vivo biodistribution of [18F]VUIIS1009A and [18F]VUIIS1009B was carried out in healthy mice with and without radioligand displacement. Dynamic PET imaging data were acquired simultaneously with [18F]VUIIS1009A/B injections in glioma-bearing rats, with binding reversibility and specificity evaluated by radioligand displacement. In vivo radiometabolite analysis was performed using radio-TLC, and quantitative analysis of PET data was performed using metabolite-corrected arterial input functions. Imaging was validated with histology and immunohistochemistry.ResultsBoth VUIIS1009A (3A) and VUIIS1009B (3B) were found to exhibit exceptional binding affinity to TSPO, with observed IC50 values against PK11195 approximately 500-fold lower than DPA-714. However, HSQC NMR suggested that VUIIS1009A and VUIIS1009B share a common binding pocket within mammalian TSPO (mTSPO) as DPA-714 and to a lesser extent, PK11195. [18F]VUIIS1009A ([18F]3A) and [18F]VUIIS1009B ([18F]3B) exhibited similar biodistribution in healthy mice. In rats bearing C6 gliomas, both [18F]VUIIS1009A and [18F]VUIIS1009B exhibited greater binding potential (k 3/k 4)in tumor tissue compared to [18F]DPA-714. Interestingly, [18F]VUIIS1009B exhibited significantly greater tumor uptake (V T) than [18F]VUIIS1009A, which was attributed primarily to greater plasma-to-tumor extraction efficiency.ConclusionsThe novel PET ligand [18F]VUIIS1009B exhibits promising characteristics for imaging glioma; its superiority over [18F]VUIIS1009A, a regioisomer, appears to be primarily due to improved plasma extraction efficiency. Continued evaluation of [18F]VUIIS1009B as a high-affinity TSPO PET ligand for precision medicine appears warranted.

Dataset Information

Synthesis and Screening in Mice of Fluorine-Containing PET Radioligands for TSPO: Discovery of a Promising ¹⁸F-Labeled Ligand.

Publications

Synthesis and Screening in Mice of Fluorine-Containing PET Radioligands for TSPO: Discovery of a Promising <sup>18</sup>F-Labeled Ligand.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Synthesis and Screening in Mice of Fluorine-Containing PET Radioligands for TSPO: Discovery of a Promising 18F-Labeled Ligand.

Publications

Synthesis and Screening in Mice of Fluorine-Containing PET Radioligands for TSPO: Discovery of a Promising &lt;sup&gt;18&lt;/sup&gt;F-Labeled Ligand.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Synthesis and Screening in Mice of Fluorine-Containing PET Radioligands for TSPO: Discovery of a Promising ¹⁸F-Labeled Ligand.

Synthesis and Screening in Mice of Fluorine-Containing PET Radioligands for TSPO: Discovery of a Promising <sup>18</sup>F-Labeled Ligand.