Prototypic 18F-Labeled Argininamide-Type Neuropeptide Y Y1R Antagonists as Tracers for PET Imaging of Mammary Carcinoma.
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SUBMITTER: Keller M
PROVIDER: S-EPMC5346983 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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.
| S-EPMC8380212 | biostudies-literature
Project description:Neuropeptide Y Y1 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 high Y1R 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 radioligands for Y1R 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 the Y1R. Three new radioligands based on BIBP3226, bearing an 18F-fluoroethoxy linker (12), an 18F-PEG-linker (13) or an 18F-fluoroglycosyl moiety (11) were radiosynthesised in high radioactivity yields. The new radioligands displayed Y1R 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 the Y1R affinities. Although 12 and 13 showed displaceable and specific binding to Y1R in vitro and in vivo, the radioligands still need to be optimised to achieve higher tumour-to-background ratios for Y1R imaging by PET. Yet the present study is another step towards an optimized PET radioligand for imaging of Y1R in vivo.
| S-EPMC6736837 | biostudies-literature
Project description:The heart failure epidemic continues to rise with coronary artery disease as one of its main causes. Novel concepts for risk stratification to guide the referring cardiologist towards revascularization procedures are of significant value. Myocardial perfusion imaging using single-photon emission computed tomography (SPECT) agents has demonstrated high accuracy for the detection of clinically relevant stenoses. With positron emission tomography (PET) becoming more widely available, mainly due to its diagnostic performance in oncology, perfusion imaging with that modality is more practical than in the past and overcomes existing limitations of SPECT MPI. Advantages of PET include more reliable quantification of absolute myocardial blood flow, the routine use of computed tomography for attenuation correction, a higher spatiotemporal resolution and a higher count sensitivity. Current PET radiotracers such as rubidium-82 (half-life, 76 s), oxygen-15 water (2 min) or nitrogen-13 ammonia (10 min) are labeled with radionuclides with very short half-lives, necessitating that stress imaging is performed under pharmacological vasodilator stress instead of exercise testing. However, with the introduction of novel 18F-labeled MPI PET radiotracers (half-life, 110 min), the intrinsic advantages of PET can be combined with exercise testing. Additional advantages of those radiotracers include, but are not limited to: potentially improved cost-effectiveness due to the use of pre-existing delivery systems and superior imaging qualities, mainly due to the shortest positron range among available PET MPI probes. In the present review, widely used PET MPI radiotracers will be reviewed and potential novel 18F-labeled perfusion radiotracers will be discussed.
| S-EPMC6454078 | biostudies-literature
Project description:PurposeThe sphingosine-1-phosphate receptor 1 (S1PR1) is an important biomarker for imaging inflammation in the central nervous system (CNS). Herein, we report our recent evaluation of four 18F-labeled S1PR1 tracers (18F-TZ43113, 18F-TZ35104, 18F-TZ4877, and 18F-TZ4881) in a rat model of multiple sclerosis (MS).ProceduresMicroPET studies of each tracer's uptake and kinetics were performed in an experimental autoimmune encephalomyelitis (EAE) rat model of MS to quantify upregulated S1PR1 expression in the lumbar spinal cord of EAE rats. Western blot analysis was conducted to confirm the differences in the expression of S1PR1 protein level between EAE and sham rats. Radiometabolite analysis was performed for the most promising candidate in rats.ResultsAll four S1PR1 tracers detected increased S1PR1 levels in response to neuroinflammation in the lumbar spinal cord of EAE rats, which was supported by western blot results. The ranked order of tracer uptake in rat spinal cord was 18F-TZ4877 > 18F-TZ4881 > 18F-TZ35104 > 18F-TZ43113. 18F-TZ4877 had the highest uptake of the four tracers and showed good kinetic modeling fits in rat spinal cord using an image-based method of arterial blood input function. Radiometabolite analysis of 18F-TZ4877 showed good in vivo stability with no major radiometabolite accumulation in the rat brain.ConclusionAmong these four new PET tracers, 18F-TZ4877 showed the most favorable profile for assessing S1PR1 expression in the EAE rat model of MS. Further characterization of these radiotracers in other models of neuroinflammation is warranted to identify a promising 18F-labeled tracer for imaging S1PR1 in vivo.
| S-EPMC7679043 | biostudies-literature
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.
| S-EPMC5634614 | biostudies-literature
Project description:Claudin 18.2 (CLDN18.2) is an emerging target for the treatment of gastric cancers. We aim to develop tracers to image the expression of CLDN18.2. A humanized nanobody targeting CLDN18.2 (clone hu19V3) was produced and labeled with 68Ga, 64Cu, and 18F. The tracers were investigated in subcutaneous and metastatic models established using two different mouse types (nude and Balb/c mice) and two different cell lines (CHO-CLDN18.2 and CT26-CLDN18.2). Gastric cancer patient-derived xenograft (PDX) models were further established for validation experiments. Three novel CLDN18.2-targeted tracers (i.e., [68Ga]Ga-NOTA-hu19V3, [64Cu]Cu-NOTA-hu19V3, and [18F]F-hu19V3) were developed with good radiochemical yields and excellent radiochemical purities. [68Ga]Ga-NOTA-hu19V3 immuno-positron emission tomography (immunoPET) rapidly delineated subcutaneous CHO-CLDN18.2 lesions and CT26-CLDN18.2 tumors, as well as showing excellent diagnostic value in PDX models naturally expressing CLDN18.2. While [68Ga]Ga-NOTA-hu19V3 had high kidney accumulation, [64Cu]Cu-NOTA-hu19V3 showed reduced kidney accumulation and improved image contrast at late time points. Moreover, [18F]F-hu19V3 was developed via click chemistry reaction under mild conditions and precisely disseminated CHO-CLDN18.2 lesions in the lungs. Furthermore, region of interest analysis, biodistribution study, and histopathological staining results correlated well with the in vivo imaging results. Taken together, immunoPET imaging with the three tracers can reliably visualize CLDN18.2 expression.
| S-EPMC9747674 | biostudies-literature
Project description:Background[18F]Fluoromisonidazole ([18F]FMISO) and 1-[18F]fluoro-3-((2-((1E,3E)-4-(6-(methylamino)pyridine-3-yl)buta-1,3-dien-1-yl)benzo[d]thiazol-6-yl)oxy)propan-2-ol ([18F]PM-PBB3 or [18F]APN-1607) are clinically used radiotracers for imaging hypoxia and tau pathology, respectively. Both radiotracers were produced by direct 18F-fluorination using the corresponding tosylate precursors 1 or 2 and [18F]F-, followed by the removal of protecting groups. In this study, we synthesized [18F]FMISO and [18F]PM-PBB3 by 18F-fluoroalkylation using [18F]epifluorohydrin ([18F]5) for clinical applications.ResultsFirst, [18F]5 was synthesized by the reaction of 1,2-epoxypropyl tosylate (8) with [18F]F- and was purified by distillation. Subsequently, [18F]5 was reacted with 2-nitroimidazole (6) or PBB3 (7) as a precursor for 18F-labeling, and each reaction mixture was purified by preparative high-performance liquid chromatography and formulated to obtain the [18F]FMISO or [18F]PM-PBB3 injection. All synthetic sequences were performed using an automated 18F-labeling synthesizer. The obtained [18F]FMISO showed sufficient radioactivity (0.83 ± 0.20 GBq at the end of synthesis (EOS); n = 8) with appropriate radiochemical yield based on [18F]F- (26 ± 7.5 % at EOS, decay-corrected; n = 8). The obtained [18F]PM-PBB3 also showed sufficient radioactivity (0.79 ± 0.10 GBq at EOS; n = 11) with appropriate radiochemical yield based on [18F]F- (16 ± 3.2 % at EOS, decay-corrected; n = 11).ConclusionsBoth [18F]FMISO and [18F]PM-PBB3 injections were successfully synthesized with sufficient radioactivity by 18F-fluoroalkylation using [18F]5.
| S-EPMC8272768 | biostudies-literature
Project description:Tryptophan (Trp) is an essential proteinogenic amino acid and metabolic precursor for several signaling molecules that has been implicated in many physiological and pathological processes. Since the two main branches of Trp metabolism-serotonin biosynthesis and kynurenine pathway-are differently affected by a variety of neurological and neoplastic diseases, selective visualization of these pathways is of high clinical relevance. However, while positron emission tomography (PET) with existing probes can be used for non-invasive assessment of total Trp metabolism, optimal imaging agents for pathway-specific PET imaging are still lacking. In this work, we describe the preparation of two 18F-labeled Trp derivatives, NIn-methyl-6-[18F]fluorotryptophan (NIn-Me-6-[18F]FTrp) and 5-hydroxy-7-[18F]fluorotryptophan (5-HO-7-[18F]FTrp). We also report feasible synthetic routes for the preparation of the hitherto unknown boronate radiolabeling precursors and non-radioactive reference compounds. Under optimized conditions, alcohol-enhanced Cu-mediated radiofluorination of the respective precursors afforded NIn-Me-6-[18F]FTrp and 5-HO-7-[18F]FTrp as application-ready solutions in radiochemical yields of 45 ± 7% and 29 ± 4%, respectively. As such, our work provides access to two promising candidate probes for pathway-specific visualization of Trp metabolism in amounts sufficient for their preclinical evaluation.
| S-EPMC10607147 | biostudies-literature
Project description:ObjectiveEpidermal growth factor receptor (EGFR) is a theranostic biomarker for a variety of cancer types. The aim of the present study was to develop an 18F radiolabeled EGFR targeting RNA aptamer, and to investigate its ability to visualize and quantify EGFR in xenograft models.MethodsBiolayer interferometry binding assay was used to detect the binding affinity of the alkyne-modified EGFR aptamer MinE07 (denoted as ME07) with recombinant human wild-type EGFR protein and the mutant EGFRvIII protein. Cy5-conjugated ME07 was used for flow cytometry and immunofluorescence staining, and an Alexa Fluor 488-labeled EGFR antibody (ab193244) was used as a control. 18F-Fluorobenzoyl (FB) azide was employed as a synthon to produce 18F-FB-ME07 via click chemistry, and the cellular uptake and internalization characteristics of 18F-FB-ME07 were investigated. Static PET scans, 60-min dynamic scans, and biodistribution study of 18F-FB-ME07 were performed in three types of tumor models.ResultsThe Kd values of ME07 to wtEGFR and EGFRvIII proteins were 0.3 nM and 271 nM respectively. The A431, U87MG, and HCT-116 cells showed strong, weak, and negative binding with Cy5-ME07, which is consistent with EGFR expression level in these cells. Peak cell uptake values of 18F-FB-ME07 in A431, U87MG and HCT-116 cells were 2.86%, 2.19% and 0.88% of the added dose respectively. The mean internalization of 18F-FB-ME07 in these cells were 60.02%, 53.1%, and 52.8% of the total accumulated radioactivity. In static PET imaging, despite high uptake in the liver and kidneys, 18F-FB-ME07 showed reasonable accumulation in A431 tumors (1.02 ± 0.13 %ID/g at 30 min after injection). Of note, the uptake of 18F-FB-ME07 in A431 xenografts was significantly higher than that in U87MG and HCT-116 xenografts. In A431 xenografted mice, the tumor/blood ratio was 3.89 and the tumor/muscle ratio reached 8.65.ConclusionsWe for the first time generated an aptamer-derived EGFR targeting PET tracer 18F-FB-ME07, which showed highly selective targeting ability in mouse tumor models expressing different levels of EGFR. Our results suggest that 18F-FB-ME07 is a potential EGFR targeting molecular imaging probe for future clinical translation.
| S-EPMC6358511 | biostudies-literature
Project description:The adenosine A2A receptor (A2AR) has emerged as a potential non-dopaminergic target for the treatment of Parkinson's disease and, thus, the non-invasive imaging with positron emission tomography (PET) is of utmost importance to monitor the receptor expression and occupancy during an A2AR-tailored therapy. Aiming at the development of a PET radiotracer, we herein report the design of a series of novel fluorinated analogs (TOZ1-TOZ7) based on the structure of the A2AR antagonist tozadenant, and the preclinical evaluation of [18F]TOZ1. Autoradiography proved A2AR-specific in vitro binding of [18F]TOZ1 to striatum of mouse and pig brain. Investigations of the metabolic stability in mice revealed parent fractions of more than 76% and 92% of total activity in plasma and brain samples, respectively. Dynamic PET/magnetic resonance imaging (MRI) studies in mice revealed a brain uptake but no A2AR-specific in vivo binding.
| S-EPMC7865263 | biostudies-literature