Application Of Positron Emission Tomography Research Articles

Development of TlBr detectors for PET imaging

Thallium bromide (TlBr) is a promising semiconductor detector material for positron emission tomography (PET) because it can offer very good energy resolution and 3D segmentation capabilities, and it also provides detection efficiency surpassing that of commonly used scintillators. Energy, timing, and spatial resolution were measured for thin (<1 mm) TlBr detectors. The energy and timing resolution were measured simultaneously for the same planar 0.87 mm-thick TlBr device. An energy resolution of (6.4 ± 1.3)% at 511 keV was achieved at −400 V bias voltage and at room temperature. A timing resolution of (27.8 ± 4.1) ns FWHM was achieved for the same operating conditions when appropriate energy gating was applied. The intrinsic spatial resolution was measured to be 0.9 mm FWHM for a TlBr detector with metallic strip contacts of 0.5 mm pitch. As material properties improve, higher bias voltage should improve timing performance. A stack of thin detectors with finely segmented readout can create a modular detector with excellent energy and spatial resolution for PET applications.

PET imaging for assessing tumor response to therapy.

Positron emission tomography (PET) is a radioisotope imaging technique capable of quantifying the regional distribution of molecular imaging probes targeted to biochemical pathways and processes allowing direct measurement of biochemical changes induced by cancer therapy, including the activity of targeted growth pathways and cellular populations. In this manuscript, we review the underlying principles of PET imaging, choices for PET radiopharmaceuticals, methods for tumor analysis and PET applications for cancer therapy response assessment including potential future directions.

Utility of FDG PET/CT in the Management of Primary Testicular Lymphoma.

Objective:Primary testicular lymphoma (PTL) is a form of extra-nodal lymphoma originating from the testicles. Currently, positron emission tomography (PET) with glucose analogue 18F-fluorodeoxyglucose (18F-FDG) is the most popular and widely used modality for evaluating tumor metabolism, and PTL usually displays increased 18F-FDG uptake. Despite the rapid increase in clinical applications of FDG PET/ computed tomography (CT), its role in PTL has neither been clearly defined nor reviewed systematically. This study reviews the usefulness and limitation of FDG PET/CT in the diagnosis and treatment of PTL.Methods:This study included 12 patients with PTL between 2004 and 2015. We retrospectively examined PET/CT results along with patient outcome. The maximum standardized uptake value (SUVmax) was calculated.Results:The mean overall survival (OS) and disease-free survival (DFS) was 44.5 months and 35.5 months, respectively. The mean SUVmax was identified as 18.5 in recurrent/metastatic group. The 1-year and 3-year OS was 94% and 69%, while the 1-year and 2-year DFS was 93.5% and 56%, respectively.Conclusion:FDG PET/CT is very helpful in both staging and evaluating treatment response. Although it is not a perfect tool in the initial diagnosis, it might aid in the differential diagnosis of challenging testicular tumors. Pre-treatment and post-treatment FDG uptake values may also have a prognostic value in patients with PTL.

A Novel Magnetic Nanoparticle for Early Detection of Amyloid Plaques in Alzheimer's Disease

Early diagnosis of Alzheimer's disease (AD) remains challenging even with the assistance of imaging. Radiation exposure limits the application of positron emission tomography (PET) for amyloid imaging. Magnetic resonance imaging (MRI) offers superior spatial resolution without the disadvantage of radiation exposure. We developed Mn0.6Zn0.4Fe2O4 (MZF) modified by Pittsburgh compound B (PiB) to specifically bind to amyloid plaques. Coated with amphiphilic nanopolymer 6sPCL-b-P(MEO2MA-co-OEGMA), PiB-MZF was stable, biocompatible, and approximately 100nm in size. The R2 relaxation rate of PiB-MZF was 169.93mM-1S-1 demonstrating excellent superparamagnetism as a T2 negative contrast agent. PiB-MZF also showed no cytotoxicity in two cell lines. Immunohistochemistry indicated successful invitro binding of PiB-MZF with Aβ plaque on 6months old AD mice brain sections. In conclusion, PiB-MZF nanoparticles are preliminarily proven to have the potential for early detection of amyloid plaques and diagnosis of AD.

Role of amino-acid PET in high-grade gliomas: limitations and perspectives.

Positron emission tomography (PET) using radiolabeled amino-acids was recently recommended by the Response Assessment in Neuro-Oncology (RANO) working group as an additional tool in the diagnostic assessment of brain tumors. The aim of this review is to summarize available literature data on the role of amino-acid PET imaging in high-grade gliomas (HGGs), with regard to diagnosis, treatment planning and follow-up of these tumors. Indeed, amino-acid PET applications are multiple throughout the evolution of HGGs. However, certain limitations such as lack of specificity, uncertain value for grading and prognostication or the limited data for treatment monitoring should to be taken into account, the latter of which are further developed in this review. Notwithstanding these limitations, amino-acid PET is becoming increasingly accessible in many nuclear medicine centers. Larger prospective cohort prospective studies are thus needed in order to increase the clinical value of this modality and enable its extended use to the largest number of patients.

Positron Emission Tomography (PET) and Pharmacokinetics: Classical Blood Sampling Versus Image-Derived Analysis of [18F]FAZA and [18F]FDG in a Murine Tumor Bearing Model.

Pharmacokinetic (PK) data are generally derived from blood samples withdrawn serially over a defined period after dosing. In small animals, blood sampling after dosing presents technical difficulties, particularly when short time intervals and frequent sampling are required. Positron emission tomography (PET) is a non-invasive functional imaging technique that can provide semi-quantitative temporal data for defined volume regions of interest (vROI), to support kinetic analyses in blood and other tissues. The application of preclinical small-animal PET to determine and compare PK parameters for [18F]FDG and [18F]FAZA, radiopharmaceuticals used clinically for assessing glucose metabolism and hypoxic fractions, respectively, in the same mammary EMT6 tumor-bearing mouse model, is reported here. Two study groups were used: normal BALB/c mice under isoflurane anesthesia were intravenously injected with either [18F]FDG or [18F]FAZA. For the first group, blood-sampling by tail artery puncture was used to collect blood samples which were then analyzed with Radio-microTLC. Dynamic PET experiments were performed with the second group of mice and analyzed for blood input function and tumor uptake utilizing a modified two compartment kinetic model. Heart and inferior vena cava vROIs were sampled to obtain image-derived data. PK parameters were calculated from blood samples and image-derived data. Time-activity curves (TACs) were also generated over regions of liver, kidney and urinary bladder to depict clearance profiles for each radiotracer. PK values generated by classical blood sampling and PET image-derived analysis were comparable to each other for both radiotracers. Heart vROI data were suitable for analysis of [18F]FAZA kinetics, but metabolic uptake of radioactivity mandated the use of inferior vena cava vROIs for [18F]FDG analysis. While clearance (CL) and blood half-life (t½) were similar for both [18F]FDG and [18F]FAZA for both sampling methods, volume of distribution yielded larger differences, indicative of limitations such as partial volume effects within quantitative image-derived data. [18F]FDG underwent faster blood clearance and had a shorter blood half-life than [18F]FAZA. Kinetic analysis of tumor uptake from PET image data showed higher uptake and longer tumor tissue retention of [18F]FDG, indicative of the tumor's glucose metabolism rate, versus lower tumor uptake and retention of [18F]FAZA. While [18F]FAZA possesses a somewhat greater hepatobiliary clearance , [18F]FDG clears faster through the renal system which results in faster radioactivity accumulation in the urinary bladder. The present study provides a working example of the applicability of functional PET imaging as a suitable tool to determine PK parameters in small animals. The comparative analysis in the current study demonstrates that it is feasible to use [18F]FDG PET and [18F]FAZA PET in the same model to analyze their blood PK parameters, and to estimate kinetic parameters for these tracers in tumor. This non-invasive imaging-based determination of tissue kinetic parameters facilitates translation from pre-clinical to clinical phases of drug development.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Design and Characterization of a 43.2-ps and PVT-Resilient TDC for Single-Photon Imaging Arrays

This brief describes the design and characterization of a ring oscillator-based time-to-digital converter (TDC) with down to 43.2 ps of time resolution and high tolerance to process, voltage and temperature variations. By employing a compact architecture, it is therefore suitable for inclusion in imaging arrays for time-stamping functions. The proposed TDC has been fabricated in a 0.13- ${\mu }\text{m}$ CMOS technology in a ${16\times 8}$ array of single-photon avalanche diode-based pixels for positron emission tomography applications and thoroughly characterized.

Recent Advances in Zirconium-89 Chelator Development.

The interest in zirconium-89 (89Zr) as a positron-emitting radionuclide has grown considerably over the last decade due to its standardized production, long half-life of 78.2 h, favorable decay characteristics for positron emission tomography (PET) imaging and its successful use in a variety of clinical and preclinical applications. However, to be utilized effectively in PET applications it must be stably bound to a targeting ligand, and the most successfully used 89Zr chelator is desferrioxamine B (DFO), which is commercially available as the iron chelator Desferal®. Despite the prevalence of DFO in 89Zr-immuno-PET applications, the development of new ligands for this radiometal is an active area of research. This review focuses on recent advances in zirconium-89 chelation chemistry and will highlight the rapidly expanding ligand classes that are under investigation as DFO alternatives.

18F-AlF Labeled Peptide and Protein Conjugates as Positron Emission Tomography Imaging Pharmaceuticals

The clinical applications of positron emission tomography (PET) imaging pharmaceuticals have increased tremendously over the past several years since the approval of 18fluorine-fluorodeoxyglucose (18F-FDG) by the Food and Drug Administration (FDA). Numerous 18F-labeled target-specific potential imaging pharmaceuticals, based on small and large molecules, have been evaluated in preclinical and clinical settings. 18F-labeling of organic moieties involves the introduction of the radioisotope by C-18F bond formation via a nucleophilic or an electrophilic substitution reaction. However, biomolecules, such as peptides, proteins, and oligonucleotides, cannot be radiolabeled via a C-18F bond formation as these reactions involve harsh conditions, including organic solvents, high temperature, and nonphysiological conditions. Several approaches, including 18F-labeled prosthetic groups, silicon, boron, and aluminum fluoride acceptor chemistry, and click chemistry have been developed, in the past, for 18F labeling of biomolecules. Linear and macrocyclic polyaminocarboxylates and their analogs and derivatives form thermodynamically stable and kinetically inert aluminum chelates. Hence, macrocyclic polyaminocarboxylates have been used for conjugation with biomolecules, such as folate, peptides, affibodies, and protein fragments, followed by 18F-AlF chelation, and evaluation of their targeting abilities in preclinical and clinical environments. The goal of this report is to provide an overview of the 18F radiochemistry and 18F-labeling methodologies for small molecules and target-specific biomolecules, a comprehensive review of coordination chemistry of Al3+, 18F-AlF labeling of peptide and protein conjugates, and evaluation of 18F-labeled biomolecule conjugates as potential imaging pharmaceuticals.

Recent progress in [11 C]carbon dioxide ([11 C]CO2 ) and [11 C]carbon monoxide ([11 C]CO) chemistry.

[11C]Carbon dioxide ([11C]CO2) and [11C]carbon monoxide ([11C]CO) are 2 attractive precursors for labelling the carbonyl position (C═O) in a vast range of functionalised molecules (eg, ureas, amides, and carboxylic acids). The development of radiosynthetic methods to produce functionalised 11C‐labelled compounds is required to enhance the radiotracers available for positron emission tomography, molecular, and medical imaging applications. Following a brief summary of secondary 11C‐precursor production and uses, the review focuses on recent progress with direct 11C‐carboxylation routes with [11C]CO2 and 11C‐carbonylation with [11C]CO. Novel approaches to generate [11C]CO using CO‐releasing molecules (CO‐RMs), such as silacarboxylic acids and disilanes, applied to radiochemistry are described and compared with standard [11C]CO production methods. These innovative [11C]CO synthesis strategies represent efficient and reliable [11C]CO production processes, enabling the widespread use of [11C]CO chemistry within the wider radiochemistry community.

The potential of radiolabeled chemotherapeutics in tumor diagnosis: Preliminary investigations with 68 Ga-gemcitabine.

Preclinical Research & Development Gemcitabine, a nucleoside analog, is a well-known chemotherapeutic drug that is used either alone or with other agents to treat a wide variety of cancers. The aim of the present work was to evaluate the potential of 68 Ga-labeled gemcitabine for its application in positron emission tomography (PET) imaging of tumorous lesions. Gemcitabine was coupled with p-NCS-benzyl-DOTA in order to facilitate radiolabeling with 68 Ga. The gemcitabine-p-NCS-benzyl-DOTA was radiolabeled with 68 Ga, obtained from a 68 Ge/68 Ga radionuclide generator. The radiolabeled product was characterized by high performance liquid chromatography (HPLC) and its tumor specificity was evaluated by biodistribution studies in Swiss mice bearing fibrosarcoma tumors. Preliminary bioevaluation study showed good tumor uptake within 1 hr post-administration [2.5% Injected Activity (IA) per g of tumor] with rapid renal clearance (>90% IA) and a high tumor to muscle ratio. 68 Ga-gemcitabine may have potential as a PET agent for tumor imaging.

Recent progress using the Staudinger ligation for radiolabeling applications.

The increasing application of positron emission tomography and single-photon emission computer tomography in radiopharmacy and nuclear medicine has stimulated the development of a multitude of novel and versatile bioorthogonal conjugation techniques. Currently, there is particular interest in radiolabeling biologically active, high molecular weight compounds like peptides, proteins, or antibodies, but also for the labeling of small organic compounds. An enormous challenge in radiolabeling these biologically active molecules is that the introduction of radiohalogens like fluorine-18 as well as various radiometals proceeds under harsh conditions, which could destroy the biomolecule. The Staudinger ligation is one of the most powerful bioorthogonal conjugation techniques. The reaction proceeds over wide temperature and pH ranges; an amide (peptide) bond is formed as the ligation unit, which minimizes distortion of the structure; no isomers are obtained; and the reaction proceeds without any metal catalyst. Due to this adaptability, this robust ligation type is a perfect candidate with a high potential for various applications in the field of radiopharmacy for the labeling of biomolecules under mild conditions. This review summarizes recent research concerning the implementation of the Staudinger ligation for radiolabeling applications.

Liquid–liquid extraction in flow of the radioisotope titanium-45 for positron emission tomography applications

The continuous liquid–liquid extraction of the PET radioisotope 45Ti using a membrane-based separator allows for efficient 45Ti recovery and radiolabeling.

Labelling with positron emitters of pnicogens and chalcogens.

The increasing importance of the positron emission tomography (PET) in clinical diagnosis led to the development of a multitude of radiotracers labelled with positron-emitting radionuclides of groups 15 (pnicogens) and 16 (chalcogens) of the periodic table of elements. The positron emitters of the endogenous occurring elements nitrogen, phosphorus, oxygen, and sulphur are characterized by very short half-lives compared with the most commonly used PET radionuclides carbon-11 or fluorine-18. Therefore, the potential of their synthesis and possible applications in PET is challenging and limited. On the other hand, the nonstandard positron emitters arsenic-72, arsenic-74, and selenium-73 have half-lives in the range of hours to days and, thus, are of interest for PET studies of processes with long biological half-lives, but novel methods have to be developed for their application, especially in the no-carrier-added state. This review summarizes recent research concerning the positron emitters of pnicogens and chalcogens for radiolabelling applications.

Novel scintillating material 2-(4-styrylphenyl)benzoxazole for the fully digital and MRI compatible J-PET tomograph based on plastic scintillators.

A novel plastic scintillator is developed for the application in the digital positron emission tomography (PET). The novelty of the concept lies in application of the 2-(4-styrylphenyl)benzoxazole as a wavelength shifter. The substance has not been used as scintillator dopant before. A dopant shifts the scintillation spectrum towards longer wavelengths making it more suitable for applications in scintillators of long strips geometry and light detection with digital silicon photomultipliers. These features open perspectives for the construction of the cost-effective and MRI-compatible PET scanner with the large field of view. In this article we present the synthesis method and characterize performance of the elaborated scintillator by determining its light emission spectrum, light emission efficiency, rising and decay time of the scintillation pulses and resulting timing resolution when applied in the positron emission tomography. The optimal concentration of the novel wavelength shifter was established by maximizing the light output and it was found to be 0.05 ‰ for cuboidal scintillator with dimensions of 14 mm x 14 mm x 20 mm.

Role of Cardiac PET in Clinical Practice

Early identification of atherosclerosis and at-risk lesions plays a critical role in reducing the burden of cardiovascular disease. While invasive coronary angiography serves as the gold standard for diagnosing coronary artery disease, non-invasive imaging techniques provide visualization of both anatomical and functional atherosclerotic processes prior to clinical presentation. The development of cardiac positron emission tomography (PET) has greatly enhanced our capability to diagnose and treat patients with early stages of atherosclerosis. Cardiac PET is a powerful, versatile non-invasive diagnostic tool with utility in the identification of high-risk plaques, myocardial perfusion defects, and viable myocardial tissue. Cardiac PET allows for comparisons of myocardial function both at time of rest and stress, providing accurate assessments of both myocardial perfusion and viability. Furthermore, novel PET techniques with unique radiotracers yield clinically relevant data on high-risk plaques in active progressive atherosclerosis. While PET exercise stress tests were previously difficult to perform given short radiotracer half-life, the development of the novel radiotracer Flurpiridaz F-18 provides a promising future for PET exercise stress imaging. In addition, hybrid imaging with computed tomography angiography (CTA) and cardiac magnetic resonance (CMR) provides integration of cardiac function and structure. In this review article, we discuss the principles of cardiac PET, the clinical applications of PET in diagnosing and prognosticating patients at risk for future cardiovascular events, compare PET with other non-invasive cardiac imaging modalities, and discuss future applications of PET in CVD evaluation and management.

Last-Step Pd-Mediated [11C]CO Labeling of a Moxestrol-Conjugated o-Iodobenzyl Alcohol: From Model Experiments to in Vivo Positron Emission Tomography Studies.

The fast, efficient, and functional group tolerant last-step radiolabeling of bioconjugates is crucial for positron emission tomography (PET) applications. In this context, o-iodobenzyl alcohol based structures were identified as ideal tags for an easy Pd-catalyzed carbonylation after bioconjugation, and a moxestrol-conjugated precursor was chosen as the model compound for the further studies. Despite scale and time constraints, conditions developed with [12C]CO and [13C]CO were easily transferred to the 11C isotope, and the desired radioactive product was obtained in amounts up to 740 MBq with radiochemical purities higher than 99%. Radio-high-performance liquid chromatography analyses of rat blood samples demonstrated excellent in vivo stability within the time of the acquisition. MicroPET-magnetic resonance imaging showed excretion pathways similar to moxestrol, and molecular modeling was also performed to evaluate the potential ability of this conjugate to bind estrogen receptors α. Thus, being both synthetically and biologically suitable, this strategy clears the path to potential novel biotracers for preclinical PET imaging.

Clinical Applications of Positron Emission Tomography for Neurosurgery(1)Current Status and Future Directions of Neuro-PET

Clinical Applications of Positron Emission Tomography for Neurosurgery(1)Current Status and Future Directions of Neuro-PET

Classics in Neuroimaging: Imaging the Dopaminergic Pathway with PET.

The success of positron emission tomography (PET) for observing molecular processes underlying brain function and disease is underpinned by radiotracer chemistry. From the earliest applications of PET to measure dopamine synthesis capacity and the abundance of neuroreceptors and transporters, to the more recent topic of dynamic neurochemical imaging, interrogation of brain dopamine in conditions such as neurodegenerative diseases, schizophrenia, mood disorders, and addictions has been a driving force that challenges the ingenuity of radiopharmaceutical scientists. In fact, the pursuit of new ligands and reaction methods to address longstanding challenges has often been pioneered in the context of dopamine imaging. From this viewpoint, we highlight the unique history of imaging the dopaminergic pathway with PET, and present our interpretation of how this worldwide effort shaped and continues to drive the field of molecular imaging.

In vivo imaging of Lyme arthritis in mice by [18F]fluorodeoxyglucose positron emission tomography/computed tomography

Objective: Lyme borreliosis (LB) is a tick-borne infectious disease caused by Borrelia burgdorferi spirochaetes, which are able to disseminate from the tick-bite site to distant organs. Mouse models are widely used to study LB and especially Lyme arthritis (LA), but only a few whole-animal in vivo imaging studies on the pathogenesis of B. burgdorferi infection in mice have been published so far. The existing imaging techniques have their drawbacks and, therefore, novel tools to complement the array of available LB imaging methodologies are needed.Method: The applicability of positron emission tomography combined with computed tomography (PET/CT) imaging was evaluated as a method to monitor LB and especially LA in the C3H/HeN mouse model infected with wild-type B. burgdorferi N40 bacteria. The imaging results were compared with the traditional LA analysis methods, such as tibiotarsal joint swelling and histopathological assessment of joint inflammation.Results: PET/CT imaging provided high-resolution images with quantitative information on the spatial and temporal distribution of the [18F]fluorodeoxyglucose ([18F]FDG) tracer in B. burgdorferi-infected mice. The [18F]FDG accumulated in the affected joints and activated lymph nodes of infected mice, while the tracer signal could not be visualized in these organs in uninfected control animals. Importantly, in vivo PET/CT imaging data were in agreement with the histopathological scoring of inflammation of mouse joints.Conclusion: PET/CT imaging with [18F]FDG is a reliable method to longitudinally monitor the development and progression of B. burgdorferi infection-induced inflammation in vivo in mouse joints.