Fluorine-18 Positron Emission Tomography Research Articles

Overcoming the obstacle of excess acetonitrile content in the final fluorine-18 radiotracers

Abstract Acetonitrile is widely used as a solvent in synthesizing various fluorine-18 positron emission tomography (PET) radiotracers. Acetonitrile is classified as a Class II residual solvent, and due to its inherent toxic properties, the quantity of residual acetonitrile in drug products has to be limited. When working under Good Manufacturing Practices (GMP) during the radiosynthesis of a radiotracer, the aim is to control all solvent concentrations contained in the ready-to-use product. All products must meet predetermined specifications. Rarely, these limits may be exceeded. To avoid eliminating the entire batch, applying a straightforward time-based technique would be desirable to allow the majority of the product to be safely used. This technique should be based on determining a specific time and volume for which the radiotracer can be utilized in the patients after completing quality control analysis. Here, we report a very simple Excel sheet program based on existing mathematical equations that calculates the exact time and volume at which the radiotracer product can be safely administered to a patient.

Discovery of Ghrelin(1-8) Analogues with Improved Stability and Functional Activity for PET Imaging.

The highest affinity ghrelin-based analogue for fluorine-18 positron emission tomography, [Inp1,Dpr3(6-FN),1Nal4,Thr8]ghrelin(1-8) amide (1), has remarkable subnanomolar receptor affinity (IC50 = 0.11 nM) toward the growth hormone secretagogue receptor 1a (GHSR). However, initial in vivo PET imaging and biodistribution of [18F]1 in mice demonstrated an unfavorable pharmacokinetic profile with rapid clearance and accumulation in liver and intestinal tissue, prompting concerns about the metabolic stability of this probe. The aims of the present study were to examine the proteolytic stability of ghrelin analogue 1 in the presence of blood and liver enzymes, structurally modify the peptide to improve stability without impeding the strong binding affinity, and measure the presently unknown functional activity of ghrelin(1-8) analogues. The in vitro stability and metabolite formation of 1 in human serum and liver S9 fraction revealed a metabolic soft spot between amino acids Leu5 and Ser6 in the peptide sequence. A focused library of ghrelin(1-8) analogues was synthesized and evaluated in a structure-activity-stability relationship study to further understand the structural importance of the residues at these positions in the context of stability and receptor affinity. The critical nature of l-stereochemistry at position 5 was identified and substitution of Ser6 with l-2,3-diaminopropionic acid led to a novel ligand with substantially improved in vitro stability while maintaining subnanomolar GHSR affinity. Despite the highly modified nature of these analogues compared to human ghrelin, ghrelin(1-8) analogues were found to recruit all G protein subtypes (Gαq/11/13/i1/oB) known to associate with GHSR as well as β-arrestins with low micromolar to nanomolar potencies. The study of these analogues demonstrates the ability to balance desirable ligand properties, including affinity, stability, and potency to produce well-rounded candidate molecules for further in vivo evaluation.

A practical guide to automating fluorine-18 PET radiochemistry using commercially available cassette-based platforms

This Tutorial Account aims to be a useful educational resource which describes how to automate fluorine-18 positron emission tomography (PET) radiochemistry using cassette-based automated radiosynthesis platforms.

Fifty Shades of Scandium: Comparative Study of PET Capabilities Using Sc-43 and Sc-44 with Respect to Conventional Clinical Radionuclides.

Scandium-44 has been proposed as a valuable radionuclide for Positron Emission Tomography (PET). Recently, scandium-43 was introduced as a more favorable option, as it does not emit high-energy γ-radiation; however, its currently employed production method results in a mixture of scandium-43 and scandium-44. The interest in new radionuclides for diagnostic nuclear medicine critically depends on the option for image-based quantification. We aimed to evaluate and compare the quantitative capabilities of scandium-43/scandium-44 in a commercial PET/CT device with respect to more conventional clinical radionuclides (fluorine-18 and gallium-68). With this purpose, we characterized and compared quantitative PET data from a mixture of scandium-43/scandium-44 (~68% scandium-43), scandium-44, fluorine-18 and gallium-68, respectively. A NEMA image-quality phantom was filled with the different radionuclides using clinical-relevant lesion-to-background activity concentration ratios; images were acquired in a Siemens Biograph Vision PET/CT. Quantitative accuracy with scandium-43/scandium-44 in the phantom’s background was within 9%, which is in agreement with fluorine-18-based PET standards. Coefficient of variance (COV) was 6.32% and signal recovery in the lesions provided RCmax (recovery coefficient) values of 0.66, 0.90, 1.03, 1.04, 1.12 and 1.11 for lesions of 10-, 13-, 17-, 22-, 28- and 37-mm diameter, respectively. These results are in agreement with EARL reference values for fluorine-18 PET. The results in this work showed that accurate quantitative scandium-43/44 PET/CT is achievable in commercial devices. This may promote the future introduction of scandium-43/44-labelled radiopharmaceuticals into clinical use.

Sulfur [18F]Fluoride Exchange Click Chemistry Enabled Ultrafast Late-Stage Radiosynthesis.

The lack of efficient [18F]fluorination processes and target-specific organofluorine chemotypes remains the major challenge of fluorine-18 positron emission tomography (PET). We report here an ultrafast isotopic exchange method for the radiosynthesis of novel PET agent aryl [18F]fluorosulfate enabled by the emerging sulfur fluoride exchange (SuFEx) click chemistry. The method has been applied to the fully automated 18F-radiolabeling of 25 structurally and functionally diverse aryl fluorosulfates with excellent radiochemical yield (83-100%, median 98%) and high molar activity (280 GBq μmol-1) at room temperature in 30 s. The purification of radiotracers requires no time-consuming HPLC but rather a simple cartridge filtration. We further demonstrate the imaging application of a rationally designed poly(ADP-ribose) polymerase 1 (PARP1)-targeting aryl [18F]fluorosulfate by probing subcutaneous tumors in vivo.

Organofluorine Compounds in Fluorine-18 Positron Emission Tomography Imaging

Organofluorine compounds are abundant in medicine and society-largely by human design and chemical synthesis, not de novo in Nature...

Structure-Affinity Relationships of 2,3,4,5-Tetrahydro-1H-3-benzazepine and 6,7,8,9-Tetrahydro-5H-benzo[7]annulen-7-amine Analogues and the Discovery of a Radiofluorinated 2,3,4,5-Tetrahydro-1H-3-benzazepine Congener for Imaging GluN2B Subunit-Containing N-Methyl-d-aspartate Receptors.

Aspiring to develop a positron emission tomography (PET) imaging agent for the GluN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), a key therapeutic target for drug development toward several neurological disorders, we synthesized a series of 2,3,4,5-tetrahydro-1H-3-benzazepine and 6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amine analogues. After in vitro testing via competition binding assay and autoradiography, [18F]PF-NB1 emerged as the best performing tracer with respect to specificity and selectivity over σ1 and σ2 receptors and was thus selected for further in vivo evaluation. Copper-mediated radiofluorination was accomplished in good radiochemical yields and high molar activities. Extensive in vivo characterization was performed in Wistar rats comprising PET imaging, biodistribution, receptor occupancy, and metabolites studies. [18F]PF-NB1 binding was selective to GluN2B-rich forebrain regions and was specifically blocked by the GluN2B antagonist, CP-101,606, in a dose-dependent manner with no brain radiometabolites. [18F]PF-NB1 is a promising fluorine-18 PET tracer for imaging the GluN2B subunits of the NMDAR and has utility for receptor occupancy studies.

Azeotropic drying-free aliphatic radiofluorination to produce PET radiotracers in a mixed organic solvent system

Efficient aliphatic radiofluorination in a mixed organic solvent system was investigated. This method obviates the time-consuming [18F]fluoride drying step routinely required in the preparation of most fluorine-18 positron emission tomography (PET) radiotracers. The [18F]fluoride ions eluted from a QMA (quaternary ammonium anion exchange) cartridge with phase transfer agents were directly mixed in various organic solvents for subsequent radiofluorination. Herein, we report the azeotropic drying-free radiofluorination of aliphatic substrates and demonstrate the viability of hydrated [18F]fluoride ions in a mixed organic solvent system for obtaining useful radiochemical yields (RCYs). This practical and simple method has demonstrated general applicability to the production of established PET tracers as well as to the rapid assessment and chemical optimization of early-stage potential radiotracers.

Decreased Bilateral FDG-PET Uptake and Inter-Hemispheric Connectivity in Multi-Domain Amnestic Mild Cognitive Impairment Patients: A Preliminary Study.

Background: Amnestic mild cognitive impairment (aMCI) is a heterogeneous condition. Based on clinical symptoms, aMCI could be categorized into single-domain aMCI (SD-aMCI, only memory deficit) and multi-domain aMCI (MD-aMCI, one or more cognitive domain deficit). As core intrinsic functional architecture, inter-hemispheric connectivity maintains many cognitive abilities. However, few studies investigated whether SD-aMCI and MD-aMCI have different inter-hemispheric connectivity pattern.Methods: We evaluated inter-hemispheric connection pattern using fluorine-18 positron emission tomography – fluorodeoxyglucose (18F PET-FDG), resting-state functional MRI and structural T1 in 49 controls, 32 SD-aMCI, and 32 MD-aMCI patients. Specifically, we analyzed the 18F PET-FDG (intensity normalized by cerebellar vermis) in a voxel-wise manner. Then, we estimated inter-hemispheric functional and structural connectivity by calculating the voxel-mirrored homotopic connectivity (VMHC) and corpus callosum (CC) subregions volume. Further, we correlated inter-hemispheric indices with the behavioral score and pathological biomarkers.Results: We found that MD-aMCI exhibited more several inter-hemispheric connectivity damages than SD-aMCI. Specifically, MD-aMCI displayed hypometabolism in the bilateral middle temporal gyrus (MTG), inferior parietal lobe, and left precuneus (PCu) (p < 0.001, corrected). Correspondingly, MD-aMCI showed decreased VMHC in MTG, PCu, calcarine gyrus, and postcentral gyrus, as well as smaller mid-posterior CC than the SD-aMCI and controls (p < 0.05, corrected). Contrary to MD-aMCI, there were no neuroimaging indices with significant differences between SD-aMCI and controls, except reduced hypometabolism in bilateral MTG. Within aMCI patients, hypometabolism and reduced inter-hemispheric connectivity correlated with worse executive ability. Moreover, hypometabolism indices correlated to increased amyloid deposition.Conclusion: In conclusion, patients with MD-aMCI exhibited the more severe deficit in inter-hemispheric communication than SD-aMCI. This long-range connectivity deficit may contribute to cognitive profiles and potentially serve as a biomarker to estimate disease progression of aMCI patients.

Evaluation of Timepix silicon detector for the detection of 18F positrons

Timepix is an evolving energy and position sensitive pixel detector. It consists of a silicon detector (sensitive layer 300 μm thick) bump-bonded to the Timepix readout chip developed by the Medipix2 collaboration. This study aims to test the feasibility of using the acquired energy and position signals from Timepix for positron imaging.The signals of the commonly used fluorine-18 PET (positron emission tomography) tracer [18F]FDG were measured using Timepix operated both in single particle counting (Medipix) and in time over threshold (TOT) modes. The spatial resolution (SR) was measured using the absorber edge method (AEM) and was calculated from the over-sampled line spread function. The track of a positron in the Timepix detector was characterized as a cluster and the energy weighted centroid of each cluster was considered as readout for the position of the positron incidence. The measurement results were compared with theoretical predictions using Monte-Carlo simulations. In addition, imaging of a tissue slice of a mouse heart was analysed with reference to standard phosphor plate imaging.Our results show that the SR was improved from 177.1±4.1 μm (centroid without energy weighting) to 155.5±3.1 μm μm (centroid with energy weighting). About 12% enhancement of SR was achieved with energy information in TOT mode. The sensitivity of Timepix was 0.35 cps/Bq based on the measurements. The measuring background and the ratio between detected positrons and gamma rays were also evaluated and were found to be consistent with theoretical predictions. A small enhancement of image quality was also achieved by applying energy information to the data of the measured tissue sample.Our results show that the inclusion of energy information could slightly enhance the positron measurement compared to without energy information and the Timepix provides a high SR and sensitivity for positron detection. Thus, Timepix is a potentially effective tool for 2D positron imaging.

Abstract 19654: Absence of Cardiovascular Implantable Electronic Device Infection in Remote Implantations Demonstrated by Fluorine-18 Positron Emission Tomography

Background: Cardiovascular implantable electronic device (CIED) infection can be very challenging and unnecessary device extraction can expose the patient to significant morbidity and mortality. Recent publications suggests that fluorine-18 ( 18 F-FDG) positron emission tomography (PET) has a high sensitivity and specificity to differentiate pocket and/or lead infections from non-infected devices older than 6 months. However, control groups were small (n≤10 patients) and the prevalence of increased 18 F-FDG uptake in not-infected CIED patients is unknown. Method: All patients with remote (&gt;6month) ICD implantation and no clinical/laboratory evidence of infection undergoing 18FDG-PET in preparation for VT ablation from 2006 to 2011 were identified in a single tertiary center. Semi-quantiative ssessment of 18 F-FDG uptake was assessed in 4 sites (generator pocked, innominate vein, superior vena cava (SVC), and intracardiac space (right atrium/ventricle). using a semi-quantitative score assessing .Uptake was categorized in none (score = 0), mild (≤thoracic background activity[t1] ; score = 1), moderate (&gt;thoracic background activity; score = 2), and severe hypermetabolism (very intense uptake; score = 3). Results: 65 contiguous patients were enrolled in this study. 18FDG PET signal uptake scores were 0 in 0%, 0%, 0%, 0% for generator pocket, innominate vein, SVC and intracardiac position, respectively. Resulting semiquantitative scores were 0.0±0.0 in (locations) and 0.1±0. Conclusion This as far as we know largest series on 18FDG PET scans in patients with remote device implantation demonstrates no incidence of increased tracer uptake in non-infected patients localized in ¼ This supports a potential use of 18 F-FDG PET/CT in differentiating patients with CIED infection from chronic implant changes, providing a new potentially new path in management of CIED infection.

Tc 99m bone scan and fluorodeoxyglucose positron emission tomography in evaluation of disseminated langerhans cell histiocytosis

Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder in which pathological langerhans cells accumulate in a variety of organs. Manifestations may include lung infiltrates, lymph node involvements, bone lesions, hepatic, hematopoietic and endocrine dysfunctions. In this case report we present fluorine-18 positron emission tomography (F-18 PET/CT) and bone scintigraphy findings of a 18-year-old male patient with disseminated LCH, mimicking multiple hypermetabolic metastatic lesions. Clinicians should be aware that LCH infiltrations can be seen as intense uptake and to differentiate infiltrations from other metastatic intense uptake with fluorodeoxyglucose PET/CT and bone scintigraphy, clinical and laboratory findings should be kept in mind.

DUODENAL DIVERTICULUM PRESENTING AS A HYPERMETABOLIC MASS ON F18-FDG PET/CT

Background: The use of fluorine-18 positron emission tomography with computed axial tomography (F-18 FDG PET/CT) is increasing in this country. This modality has shown to be an accurate test for the diagnosis and staging of various primary and metastatic malignancies to include colorectal carcinoma. Although false positives can be seen with various non-malignant processes, including infectious and inflammatory conditions, duodenal diverticuli causing false positive uptake on PET/CT has not yet been described in the literature. We report the first case report of this finding. Case: The patient was an 80-year-old woman with a history of stage I breast cancer status post modified mastectomy and tamoxifen treatment for 5 years. She was felt to be in remission when a routine blood test showed mild elevation in alkaline phosphatase. After initial work up, an F-18 FDG PET/CT was performed to further evaluate this finding, which showed a focus of abnormal radiotracer accumulation adjacent to the duodenal sweep with a delayed standardized uptake value (SUV-m) of 7.10. This focus of activity corresponded to a round 3 cm lesion on CT. As the PET/CT findings were suggestive of a neoplasm, further endoscopic evaluation with an EGD and EUS was performed. EGD using a front viewing scope showed no abnormalities in the duodenum. The EUS confirmed a 2.8 by 3.0 cm hypoechoic, well-circumscribed, fluid filled, cystic lesion adjacent to the duodenal sweep corresponding to the finding on PET/CT. On review of this area with the side-viewing camera on EUS, a duodenal diverticulum was identified which matched these findings. Discussion: PET/CT is becoming more commonly used for various malignancies. Although it is a very sensitive imaging test for hypermetabolic malignancies, there are several reported false positives, especially with infectious and inflammatory processes which utilize glucose metabolism. To date, there has not been a report of false postive F-18 FDG uptake within a duodenal diverticulum. Given that duodenal diverticulum are relatively common, it may be important to consider it as a possible source of false positives by endoscopist who evaluate these patients Conclusion: Duodenal diverticului are common and typically asymptomatic. They may be a source of false positive F-18 FDG PET/CT scans. Endoscopists need to become more familiar with this possible source of abnormal PET findings as this modality becomes more widespread in the evaluation of oncology patients.

Neuroimaging in cerebrovascular disorders: Measurement of cerebral physiology after stroke and assessment of stroke recovery

Nuclear medicine imaging can play an important role in the diagnosis of stroke risk, the differential diagnosis of vascular and parenchymal cerebral abnormalities, and the understanding and management of poststroke recovery. Radionuclide brain-imaging methods can assess hemodynamic, vascular, and metabolic status before and after stroke. Several techniques, including vasodilatory stress imaging with regional cerebral blood flow (rCBF) single-photon emission computed tomography (SPECT), oxygen extraction methods with positron emission tomography (PET), and spectroscopic imaging with magnetic resonance spectroscopic imaging, offer ways to distinguish vascular from parenchymal dysfunction and to determine whether any observed abnormalities in cerebral blood flow are primary or secondary disease manifestations. The value of radionuclide imaging in assessing the efficacy of several interventional surgical procedures is presented. Data from several imaging modalities bearing on the controversial issue of luxury perfusion and reperfusion injury are analyzed, including some of the discrepancies between animal and human clinical data. Imaging evidence for white matter disease and microangiopathy is analyzed, including a quantitative rCBF pattern analysis that distinguishes between typical Alzheimer's disease and microangiopathy by using multivariate analysis of variance curve profile analysis, which shows results of significant differences in the circumferential cortical blood flow profiles at P =.01. Microangiopathy showed rCBF reduction in the frontal and frontotemporal regions as compared with the more typical reduction in posterior temporal-parietal rCBF diminution characteristic of Alzheimer's disease. Several functional neuroimaging approaches to the study of cerebral poststroke reorganization are analyzed in the context of 2 major models of recovery: the resolution of diaschisis and reorganization in spared brain. Research on these issues is presented with SPECT, PET, magnetic resonance imaging, and magnetic resonance spectroscopy. Data show how standard structural magnetic resonance imaging, (99m)Tc hexamethylpropylene amine oxime SPECT, PET imaging, and magnetic resonance spectroscopy can be used to identify the extent of permanent damage versus penumbral and remote effects of a stroke. The results of the analysis of the pure-diaschisis model show a high correlation between the rCBF brain SPECT defect volume in the cortex and the magnetic resonance spectroscopic imaging (MRSI) change in the white matter. There is a statistically significant positive correlation between the 2 (P <.01; r(2) = 0.94). The increased creatine/N-acetyl aspartate and reduced rCBF are proposed to be due to an increase in the white matter creatine component due to diaschisis and the repair mechanisms associated with increased astrocytosis, in addition to a reduction of N-acetyl aspartate in diaschitic white matter. Xenon-133 dynamic SPECT is shown to be a quantitative and sensitive measure of cerebrovascular status and hemodynamic constraints in both spared and affected brain, providing evidence for reorganization and cerebral plasticity. Fluorine-18 PET and (31)P spectroscopic imaging data show reorganizational changes in the contralesional hemisphere after stroke. The phosphocreatine-adenosine triphosphate ratio in the contralesional hemisphere was 38% +/- 17% higher than in the ipsilateral hemisphere. The phosphocreatine-adenosine triphosphate ratio was highly correlated (r = 0.88, P <.05) with increasing (18)F-fluorodeoxyglucose uptake. These results showed that there is a parallel change in glucose metabolism and high-energy phosphate metabolism associated with poststroke recovery that is proposed to be due to cerebral reorganization in the contralateral premotor cortex. The value of these results on rehabilitation strategy, including possible criteria for the use of facilitatory versus compensatory approaches, is analyzed.

Early and late stage positron emission tomography (PET) studies on the haemocirculation and metabolism of seemingly normal brain tissue in patients with gliomas following radiochemotherapy.

Haemocirculatory and metabolic changes in seemingly normal brain tissue following radiochemotherapy including nimustine hydrochloride (ACNU) and tegafur (FT) were analyzed using oxygen-15 and fluorine-18 positron emission tomography (PET) in seven patients with gliomas. At an early stage (within one month) after radiochemotherapy, marginal increases in regional cerebral blood flow (rCBF) and cerebral blood volume (rCBV) were found contralateral to the tumour in gray matter which was apparently normal brain structure, as seen on computerized tomography (CT). The oxygen extraction fraction (rOEF) decreased significantly (p less than 0.05 by a paired-t test) from that of the pretreatment study, due to surgical decompression and radiochemotherapy. At the late stage (three to thirty-one months with a mean of thirteen months), rCBF decreased significantly from the early stage study (p less than 0.05); oxygen consumption (rCMRO2) fell in all cases significantly from the pretreatment study (p less than 0.01) and from the early stage study (p less than 0.05); consequently, rOEF remained unchanged at a level similar to the early stage study. Glucose consumption (rCMRG1) increased slightly as compared with the early stage study but failed to be restored to the level of the pretreatment study. Noteworthy was a coupling reduction of rCBF and rCMRO2--presumably, a late delayed effect of radiochemotherapy. These preliminary results indicate that with PET studies it may be possible to predict damage to normal brain tissue after radiochemotherapy.

Positron emission tomographic evaluation of radiochemotherapeutic effect on regional cerebral hemocirculation and metabolism in patients with gliomas.

Hemocirculatory and metabolic changes in tumor regions and the remote brain structure were analyzed using oxygen-15 and fluorine-18 positron emission tomography (PET) in eight patients with gliomas after radiation and chemotherapy of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) and N-(2-tetrahydrofuryl)-5-fluorouracil (FT-207). In the tumor regions after the radiochemotherapy, regional cerebral blood flow (rCBF) and cerebral blood volume (rCBV) varied widely and there was a tendency for oxygen consumption (rCMRO2) to fall. The change in glucose consumption (rCMRG1) was especially noteworthy with regard to clinical correlations. Six patients with decreased rCMRG1 values had 16% to 29% regressions in tumor size measured by X-ray computerized tomography (CT), and showed some period of clinical relief. In contrast, one patient with an increased rCMRG1 value had some progression of tumor growth, and there were no clinical amelioration. The hemocirculation and metabolism of the contralateral gray matter seem to fluctuate by various factors as intracranial pressure and the effectiveness of the therapy. In gliomas therapy, tumor rCMRG1 values can be a good indicator of therapeutic effectiveness.