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Moving into the next era of PET myocardial perfusion imaging: introduction of novel 18F-labeled tracers.

ABSTRACT: 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.

SUBMITTER: Werner RA

PROVIDER: S-EPMC6454078 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Moving into the next era of PET myocardial perfusion imaging: introduction of novel <sup>18</sup>F-labeled tracers.

Werner Rudolf A RA Chen Xinyu X Rowe Steven P SP Lapa Constantin C Javadi Mehrbod S MS Higuchi Takahiro T

The international journal of cardiovascular imaging 20181017 3

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 ...[more]

PMID: 30334228

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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.

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.

Project description:PurposeCharacteristic features of amyloid-PET (A), tau-PET (T), and FDG-PET (N) can serve for the A/T/N classification of neurodegenerative diseases. Recent studies showed that the early, perfusion-weighted phases of amyloid- or tau-PET recordings serve to detect cerebrometabolic deficits equally to FDG-PET, therefore providing a surrogate of neuronal injury. As such, two channels of diagnostic information can be obtained in the setting of a single PET scan. However, there has hitherto been no comparison of early-phase amyloid- and tau-PET as surrogates for deficits in perfusion/metabolism. Therefore, we undertook to compare [18F]flutemetamol-amyloid-PET and [18F]PI-2620 tau-PET as "one-stop shop" dual purpose tracers for the detection of neurodegenerative disease.MethodsWe obtained early-phase PET recordings with [18F]PI-2620 (0.5-2.5 min p.i.) and [18F]flutemetamol (0-10 min p.i.) in 64 patients with suspected neurodegenerative disease. We contrasted global mean normalized images (SUVr) in the patients with a normal cohort of 15 volunteers without evidence of increased pathology to β-amyloid- and tau-PET examinations. Regional group differences of tracer uptake (z-scores) of 246 Brainnetome volumes of interest were calculated for both tracers, and the correlations of the z-scores were evaluated using Pearson's correlation coefficient. Lobar compartments, regions with significant neuronal injury (z-scores < - 3), and patients with different neurodegenerative disease entities (e.g., Alzheimer's disease or 4R-tauopathies) served for subgroup analysis. Additionally, we used partial regression to correlate regional perfusion alterations with clinical scores in cognition tests.ResultsThe z-scores of perfusion-weighted images of both tracers showed high correlations across the brain, especially in the frontal and parietal lobes, which were the brain regions with pronounced perfusion deficit in the patient group (R = 0.83 ± 0.08; range, 0.61-0.95). Z-scores of individual patients correlated well by region (R = 0.57 ± 0.15; range, 0.16-0.90), notably when significant perfusion deficits were present (R = 0.66 ± 0.15; range, 0.28-0.90).ConclusionThe early perfusion phases of [18F]PI-2620 tau- and [18F]flutemetamol-amyloid-PET are roughly equivalent indices of perfusion defect indicative of regional and lobar neuronal injury in patients with various neurodegenerative diseases. As such, either tracer may serve for two diagnostic channels by assessment of amyloid/tau status and neuronal activity.

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.

Project description:IntroductionGlucose has been deemed the driving force of tumor growth for decades. However, research has shown that several tumors metabolically shift towards glutaminolysis. The development of radiolabeled glutamine derivatives could be a useful molecular imaging tool for visualizing these tumors. We elaborated on the glutamine-derived PET tracers by developing two novel probes, namely [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine.Materials and methodsBoth tracers were labelled with fluorine-18 using our recently reported ruthenium-based direct aromatic fluorination method. Their affinity was evaluated with a [3H]glutamine inhibition experiment in a human PC-3 and a rat F98 cell line. The imaging potential of [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine was tested using a mouse PC-3 and a rat F98 tumor model.ResultsThe radiosynthesis of both tracers was successful with overall non-decay corrected yields of 18.46 ± 4.18% (n = 10) ([18F]fluorophenylglutamine) and 8.05 ± 3.25% (n = 5) ([18F]fluorobiphenylglutamine). In vitro inhibition experiments showed a moderate and low affinity of fluorophenylglutamine and fluorobiphenylglutamine, respectively, towards the human ASCT-2 transporter. Both compounds had a low affinity towards the rat ASCT-2 transporter. These results were endorsed by the in vivo experiments with low uptake of both tracers in the F98 rat xenograft, low uptake of [18F]FBPG in the mice PC-3 xenograft and a moderate uptake of [18F]FPG in the PC-3 tumors.ConclusionWe investigated the imaging potential of two novel PET radiotracers [18F]FPG and [18F]FBPG. [18F]FPG is the first example of a glutamine radiotracer derivatized with a phenyl group which enables the exploration of further derivatization of the phenyl group to increase the affinity and imaging qualities. We hypothesize that increasing the affinity of [18F]FPG by optimizing the substituents of the arene ring can result in a high-quality glutamine-based PET radiotracer. Advances in Knowledge and Implications for patient care: We hereby report novel glutamine-based PET-tracers. These tracers are tagged on the arene group with fluorine-18, hereby preventing in vivo defluorination, which can occur with alkyl labelled tracers (e.g. (2S,4R)4-[18F]fluoroglutamine). [18F]FPG shows clear tumor uptake in vivo, has no in vivo defluorination and has a straightforward production. We believe this tracer is a good starting point for the development of a high-quality tracer which is useful for the clinical visualization of the glutamine transport.

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Moving into the next era of PET myocardial perfusion imaging: introduction of novel 18F-labeled tracers.

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Moving into the next era of PET myocardial perfusion imaging: introduction of novel <sup>18</sup>F-labeled tracers.

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