Investigation of Cerebral O-(2-[18F]Fluoroethyl)-L-Tyrosine Uptake in Rat Epilepsy Models

Molecular Imaging and Biology - A recent study reported on high, longer lasting and finally reversible cerebral uptake of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) induced by epileptic activity....     

Tracer Level Electrophilic Synthesis and Pharmacokinetics of the Hypoxia Tracer [18F]EF5

Purpose  

2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide labeled with [¹⁸F]-fluorine ([¹⁸F]EF5), a promising tracer for tumor hypoxia, has previously been synthesized in low yields and low specific radioactivity. In pharmacokinetic evaluations, in the presence of non-radioactive EF5, a uniform and low background uptake and high in vivo stability of [¹⁸F]EF5 have been demonstrated. Our purpose was to increase the specific radioactivity of [¹⁸F]EF5 to enable to study the pharmacokinetics at trace level.     

Evaluation of [18F]-CP18 as a PET Imaging Tracer for Apoptosis

Purpose

We identified and validated [¹⁸F]-CP18, a DEVD (the caspase 3 substrate recognition motif) containing substrate-based compound as an imaging tracer for caspase-3 activity in apoptotic cells.

Procedures

CP18 was radiolabeled with fluorine-18 using click chemistry. The affinity and selectivity of CP18 for caspase-3 were evaluated in vitro. The biodistribution and metabolism pattern of [¹⁸F]-CP18 were assessed in vivo. [¹⁸F]-CP18 positron emission tomography (PET) scans were performed in a dexamethasone-induced thymic apoptosis mouse model. After imaging, the mice were sacrificed, and individual organs were collected, measured in a gamma counter, and tested for caspase-3 activity.

Results

In vitro enzymatic caspase-3 assay demonstrated specific cleavage of CP18. In vivo, [¹⁸F]-CP18 is predominantly cleared through the kidneys and urine, and is rapidly eliminated from the bloodstream. There was a sixfold increase in caspase activity and a fourfold increase of [¹⁸F]-CP18 retention in the dexamethasone-induced thymus of treated versus control mice.

Conclusions

We report the use [¹⁸F]-CP18 as a PET tracer for imaging apoptosis. Our data support further development of this tracer for clinical PET applications.     

Modeling of [18F]FEOBV Pharmacokinetics in Rat Brain

Molecular Imaging and Biology - [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV) is a radioligand for the vesicular acetylcholine transporter (VAChT), a marker of the cholinergic system. We evaluated...     

Quantification of [18F]UCB-H Binding in the Rat Brain: From Kinetic Modelling to Standardised Uptake Value

Molecular Imaging and Biology - [18F]UCB-H is a specific positron emission tomography (PET) biomarker for the Synaptic Vesicle protein 2A (SV2A), the binding site of the antiepileptic drug...     

Evaluation of Tracer Kinetic Models for Analysis of [18F]FDDNP Studies

Purpose  Different pharmacokinetic methods for [¹⁸F]FDDNP studies were evaluated using both simulations and clinical data. Procedures  Methods included two-tissue reversible plasma (2T4k), simplified reference tissue input (SRTM), and a modified 2T4k models. The latter included an additional compartment for metabolites (2T1M). For plasma input models, binding potential, BP_ND, was obtained both directly (=k ₃/k ₄) and indirectly (using volume of distribution ratios). Results  For clinical data, 2T1M was preferred over 2T4k according to Akaike criterion. Indirect BP_ND using 2T1M correlated better with SRTM then direct BP_ND. Fairly constant volume of distribution of metabolites was found across brain and across subjects, which was strongly related to bias in BP_ND obtained from SRTM as seen in simulations. Furthermore, in simulations, SRTM showed constant bias with best precision if metabolites entered brain. Conclusions  SRTM is the method of choice for quantitative analysis of [¹⁸F]FDDNP even if it is unclear whether labeled metabolites enter the brain.     

Influence of Dexamethasone on O-(2-[18F]-Fluoroethyl)-l-Tyrosine Uptake in the Human Brain and Quantification of Tumor Uptake

Molecular Imaging and Biology - O-(2-[18F]fluoroethyl)-l-tyrosine ([18F]FET) is an established positron emission tomography (PET) tracer for brain tumor imaging. This study explores the influence...     

Relationship Between Clinicopathological Characteristics and PET/CT Uptake in Esophageal Squamous Cell Carcinoma: [18F]Alfatide versus [18F]FDG

Molecular Imaging and Biology - To assess a novel radiotracer aluminum [18F]fluoride-1,4,7-triazacyclononane-triacetic acid-pegylated dimeric RGD ([18F]ALF-NOTA-PRGD2, denoted as [18F]Alfatide) for...     

Extraction of Input Function from Rat [18F]FDG PET Images

Purpose  

Small animal positron emission tomography (PET) with 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) facilitates the visualization and quantification of glucose uptake in rats and mice. The quantification of glucose uptake requires an input function, which is generally obtained by measuring radioactivity in arterial plasma withdrawn during PET imaging; however, this approach is not always feasible because abundant blood sampling may affect the physiological process being measured. The purpose of the present study was to develop a new model-based technique (K-Model) and compare it to the previous F-Model.     

Tantalum [18O]water target for the production of [18F]fluoride with high reactivity for the preparation of 2-deoxy-2-[18F]fluoro-D-glucose.

PURPOSE: To develop a new tantalum [18O]water target for the routine production of reactive, no-carrier-added [18F]fluoride ion in Curie amounts for the synthesis of radiopharmaceuticals. PROCEDURES: The tantalum target body was filled with 0.86 mL of 95% enriched [18O]water and irradiated with 10.2 MeV protons on target with beam currents of 26-40 microA for 60-90 min. [18F]Fluoride ion produced is trapped in an anion exchange resin cartridge and the expensive [18O]water is recovered for recycling. The [18F]fluoride ion is released from the resin by elution with a dilute solution of K(2)CO(3) and utilized in the synthesis of 2-deoxy-2-[18F]fluoro-D-glucose (FDG). RESULTS: Using the tantalum target, Curie levels of no-carrier-added [18F]fluoride ion (specific activity: >30,000 Ci/mmol) were reliably and reproducibly produced (n > 100), from which FDG was synthesized in 70% radiochemical yield. CONCLUSION: Tantalum [18O]water target body for the production of [18F]fluoride ion has the best characteristics from the standpoint of [18F]fluoride ion recovery and its radiochemical reactivity and low induced activation. This new target has the potential to replace the currently used silver and titanium [18O]targets for the routine production of [18F]fluoride ion.     

PET Imaging of the P2X7 Ion Channel with a Novel Tracer [18F]JNJ-64413739 in a Rat Model of Neuroinflammation

Molecular Imaging and Biology - The P2X7 receptor, an adenosine triphosphate (ATP)-gated purinoreceptor, has emerged as one of the key players in neuroinflammatory processes. Therefore, developing...     

Dexamethasone-Induced Insulin Resistance: Kinetic Modeling Using Novel PET Radiopharmaceutical 6-Deoxy-6-[18F]fluoro-d-glucose

Purpose

An insulin-resistant rat model, induced by dexamethasone, was used to evaluate a Michaelis–Menten-based kinetic model using 6-deoxy-6-[¹⁸F]fluoro-d-glucose (6-[¹⁸F]FDG) to quantify glucose transport with PET.

Procedures

Seventeen, male, Sprague–Dawley rats were studied in three groups: control (Ctrl), control?+?insulin (Ctrl?+?I), and dexamethasone?+?insulin (Dex?+?I). PET scans were acquired for 2 h under euglycemic conditions in the Ctrl group and under hyperinsulinemic-euglycemic conditions in the Ctrl?+?I and Dex?+?I groups.

Results

Glucose transport, assessed according to the 6-[¹⁸F]FDG concentration, was highest in skeletal muscle in the Ctrl?+?I, intermediate in the Dex?+?I, and lowest in the Ctrl group, while that in the brain was similar among the groups. Modeling analysis applied to the skeletal muscle uptake curves yielded values of parameters related to glucose transport that were greatest in the Ctrl?+?I group and increased to a lesser degree in the Dex?+?I group, compared to the Ctrl group.

Conclusion

6-[¹⁸F]FDG and the Michaelis–Menten-based model can be used to measure insulin-stimulated glucose transport under basal and an insulin resistant state in vivo.     

6-[F-18]Fluoro-l-DOPA Positron Emission Tomography in the Imaging of Merkel Cell Carcinoma: Preliminary Report of Three Cases with 2-Deoxy-2-[F-18]Fluoro-d-Glucose Positron Emission Tomography or Pentetreotide-(111In) SPECT Data

Purpose Merkel cell carcinoma (MCC) is an uncommon and aggressive cutaneous neoplasm of neuroendocrine origin. Somatostatin receptor scintigraphy (SRS) and positron emission tomography (PET) using 2-deoxy-2-[F-18]fluoro-d-glucose (FDG) have been proposed to stage MCC and to detect early recurrences. As 6-[F-18]fluoro-l-DOPA (FDOPA) is taken up by other neuroendocrine tumors, we speculated that FDOPA-PET could image MCC. Procedure FDOPA-PET was performed together with FDG-PET (three patients) and SRS (two patients) in different clinical settings: localization of the primary tumor, staging, and suspicion of recurrence. Results Uptake of FDOPA-(18F) by MCC was observed in the two true-positive cases, with an agreement between the results of FDOPA-PET, FDG-PET, and SRS; however, the contrast was lower on FDOPA-PET than on FDG-PET images. In the last patient suspected of recurrence repeatedly on SRS and with inconclusive FDG-PET, FDOPA-PET was negative, and a 12-month follow-up demonstrated a true-negative result. Conclusion MCC takes up FDOPA-(18F). The potential role of FDOPA-PET in its management warrants clarification.     

An Efficient Automated Radiosynthesis and Bioactivity Confirmation of VMAT2 Tracer [18F]FP-(+)-DTBZ

Purpose

The aim of this study was to optimize the radiolabeling method of [¹⁸F]fluoropropyl-(+)-dihydrotetrabenazine ([¹⁸F]FP-(+)-DTBZ) to fulfill the demand of preclinical and clinical application.

Procedures

Optimized labeling conditions were performed by altering the molar ratio of precursor to base (P/B), base species, solvents, reaction temperature, reaction time, and precursor concentration through manual radiosynthesis of [¹⁸F]FP-(+)-DTBZ. The conditions with the highest radiochemical yield (RCY) were applied to automated radiosynthesis, and the crude product was purified with a Sep-Pak Plus C18 cartridge. Quality control and stability of [¹⁸F]FP-(+)-DTBZ were carried out by HPLC. In vitro cellular uptake and blocking assays were conducted in human neuroblastoma cell line SH-SY5Y. In vivo imaging with small animal positron emission tomography (microPET) was performed with Sprague–Dawley rats.

Results

Under the optimized conditions (P/K₂CO₃?=?1:8, heating at 120 °C for 3 min in dimethyl sulfoxide), an RCY of 88.7 % was obtained with 1.0 mg precursor. The optimized reaction conditions were successfully applied to an automated module and gave a high activity yield (AY) of 30–55 % in about 40 min with a >?99.0 % radiochemical purity (RCP) and a >?44.4 GBq/μmol molar activity (A_m). Stability test displayed that the RCP retained >?98.0 % in 8 h in saline and in phosphate buffer saline (PBS, pH 7.4). In vitro cellular uptake assay showed accumulation of [¹⁸F]FP-(+)-DTBZ in SH-SY5Y cells, which could be significantly inhibited by vesicular monoamine transporter 2 (VMAT2) inhibitor DTBZ. MicroPET images of rat brain displayed that the striatum showed the highest uptake with a standardized uptake value (SUV) of 3.91?±?0.30 at ~?70 min. Co-injection with DTBZ (1.0 mg/kg) resulted in a 75 % decrease of the striatal SUV, confirming the specificity of [¹⁸F]FP-(+)-DTBZ to VMAT2.

Conclusions

We obtained an optimized radiolabeling method of [¹⁸F]FP-(+)-DTBZ and successfully applied it to a commercial available module. The automated synthesis gave a high AY and RCP of [¹⁸F]FP-(+)-DTBZ with high and specific binding to VMAT2, facilitating its routine application for VMAT2 tracing.

     

Whole-Body [18F]FDG-PET/MRI vs. [18F]FDG-PET/CT in Malignant Melanoma

Purpose

To assess the diagnostic performance of simultaneous whole-body 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) positron emission tomography (PET)/magnetic resonance imaging (MRI) compared to [¹⁸F]FDG PET/x-ray computed tomography (CT) for detection of distant metastatic disease in patients with malignant melanoma.

Procedures

We included patients with malignant melanoma who underwent a single injection [¹⁸F]FDG dual-imaging protocol that included whole-body PET/CT and subsequent whole-body PET/MRI for staging or restaging purposes in a prospective setting. Images from both modalities were analyzed by two rater teams for the presence of metastatic lesions. PET/CT–PET/MRI overall agreement as well as region-based accuracies, sensitivities (Se), and specificities (Sp) were computed.

Results

Between July 2014 and December 2018, 22 patients were enrolled. Interrater agreement and overall accuracy (consensus reading) were 78.8 % (95 % CI 71–84.9) and 96.1 % (95 % CI 92.3–98) for PET/MRI and 78 % (70.2–84.3) and 97.4 % (95 % CI 93.7–98.9) for PET/CT, respectively (P?=?0.42). PET/MRI reached a region-based Se of 89.1 % (95 % CI 79.4–94.5) and a Sp of 100 %, whereas PET/CT showed a region-based Se of 92.7 % (95 % CI 84–96.9) and a Sp of 100 % for the detection of metastatic disease in malignant melanoma.

Conclusions

Whole-body [¹⁸F]FDG-PET/MRI appears to be comparable to [¹⁸F]FDG-PET/CT for lesion detection in patients with malignant melanoma.

     

Feasibility of Assessing [18F]FDG Lung Metabolism with Late Dynamic PET Imaging

Purpose  

The aim of this work was to non-invasively establish the feasibility of assessing 2-deoxy-2-[¹⁸F]fluoro-D-glucose (¹⁸F-FDG) lung metabolism with the use of a late dynamic positron emission tomograpy (PET) acquisition, i.e., beyond 2 h after injection.     

The Effect of Chirality on the Application of 5-[18F]Fluoro-Aminosuberic Acid ([18F]FASu) for Oxidative Stress Imaging

Molecular Imaging and Biology - The cystine transporter, system xC-, plays a crucial role in sustaining redox homeostasis and is reported to be overexpressed in several cancer subtypes....     

On-demand radiosynthesis of N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) on an electrowetting-on-dielectric microfluidic chip for 18F-labeling of protein

An all-electronic, droplet-based batch microfluidic device, operated using the electrowetting on dielectric (EWOD) mechanism was developed for on-demand synthesis of N-succinimidyl-4-[¹⁸F]fluorobenzoate ([¹⁸F]SFB), the most commonly used ¹⁸F-prosthetic group for biomolecule labeling. In order to facilitate the development of peptides, and proteins as new diagnostic and therapeutic agents, we have diversified the compact EWOD microfluidic platform to perform the three-step radiosynthesis of [¹⁸F]SFB starting from the no carrier added [¹⁸F]fluoride ion. In this report, we established an optimal microliter droplet reaction condition to obtain reliable yields and synthesized [¹⁸F]SFB with sufficient radioactivity for subsequent conjugation to the anti-PSCA cys-diabody (A2cDb) and for small animal imaging. The three-step, one-pot radiosynthesis of [¹⁸F]SFB radiochemistry was adapted to a batch microfluidic platform with a reaction droplet sandwiched between two parallel plates of an EWOD chip, and optimized. Specifically, the ratio of precursor to base, droplet volume, reagent concentration, reaction time, and evaporation time were found be to be critical parameters. [¹⁸F]SFB was successfully synthesized on the EWOD chip in 39 ± 7% (n = 4) radiochemical yield in a total synthesis time of ∼120 min ([¹⁸F]fluoride activation, [¹⁸F]fluorination, hydrolysis, and coupling reaction, HPLC purification, drying and reformulation). The reformulation and stabilization step for [¹⁸F]SFB was important to obtain a high protein labeling efficiency of 33.1 ± 12.5% (n = 3). A small-animal immunoPET pilot study demonstrated that the [¹⁸F]SFB-PSCA diabody conjugate showed specific uptake in the PSCA-positive human prostate cancer xenograft. The successful development of a compact footprint of the EWOD radiosynthesizer has the potential to empower biologists to produce PET probes of interest themselves in a standard laboratory.

An all-electronic, droplet-based batch microfluidic device, operated using the electrowetting on dielectric (EWOD) mechanism was developed for on-demand synthesis of acommonly used ¹⁸F-prosthetic group for biomolecule labeling.