Molecular imaging is an attractive modality that has been widely employed in many aspects of biomedical research; especially those aimed at the early detection of diseases such as cancer, inflammation and neurodegenerative disorders. The field emerged in response to a new research paradigm in healthcare that seeks to integrate detection capabilities for the prediction and prevention of diseases. This approach made a distinct impact in biomedical research as it enabled researchers to leverage the capabilities of molecular imaging probes to visualize a targeted molecular event non-invasively, repeatedly and continuously in a living system. In addition, since such probes are inherently compact, robust, and amenable to high-throughput production, these probes could potentially facilitate screening of preclinical drug discovery, therapeutic assessment and validation of disease biomarkers. They could also be useful in drug discovery and safety evaluations. In this review, major trends in the chemical synthesis and development of positron emission tomography (PET), optical and magnetic resonance imaging (MRI) probes are discussed.
Positron emission tomography; radiochemistry; MRI; optical probes; molecular imaging
Synthetic nanoparticles are emerging as versatile tools in biomedical applications, particularly in the area of biomedical imaging. Nanoparticles 1 – 100 nm in diameter have dimensions comparable to biological functional units. Diverse surface chemistries, unique magnetic properties, tunable absorption and emission properties, and recent advances in the synthesis and engineering of various nanoparticles suggest their potential as probes for early detection of diseases such as cancer. Surface functionalization has expanded further the potential of nanoparticles as probes for molecular imaging.
To summarize emerging research of nanoparticles for biomedical imaging with increased selectivity and reduced nonspecific uptake with increased spatial resolution containing stabilizers conjugated with targeting ligands.
This review summarizes recent technological advances in the synthesis of various nanoparticle probes, and surveys methods to improve the targeting of nanoparticles for their application in biomedical imaging.
Structural design of nanomaterials for biomedical imaging continues to expand and diversify. Synthetic methods have aimed to control the size and surface characteristics of nanoparticles to control distribution, half-life and elimination. Although molecular imaging applications using nanoparticles are advancing into clinical applications, challenges such as storage stability and long-term toxicology should continue to be addressed.
biomedical imaging; molecular imaging; nanoparticle synthesis; surface modification; targeting
Rapid advances in biomedical sciences in recent years have drastically accelerated the discovery of the molecular basis of human diseases. The great challenge is how to translate the newly acquired knowledge into new medicine for disease prevention and treatment. Drug discovery is a long and expensive process and the pharmaceutical industry has not been very successful at it despite its enormous resources and spending on the process. It is increasingly realized that academic biomedical research institutions ought to be engaged in early stage drug discovery, especially when it can be coupled to their basic research. To leverage the productivity of new drug development a substantial acceleration in validation of new therapeutic targets is required, which would require small molecules that can precisely control target functions in complex biological systems in a temporal and dose-dependent manner. In this review, we describe a process of integration of small molecule discovery and chemistry in academic biomedical research, which will ideally bring together the elements of innovative approaches to new molecular targets; existing basic and clinical research; screening infrastructure; and synthetic and medicinal chemistry to follow-up on small molecule hits. Such integration of multi-disciplinary resources and expertise will enable academic investigators to discover novel small molecules that are expected to facilitate their efforts in both mechanistic research and new drug target validation. More broadly academic drug discovery should contribute new entities to therapy for intractable human diseases especially for orphan diseases, and hopefully stimulate and synergize with the commercial sector.
Small molecule; drug discovery; chemical screening; medicinal chemistry
Monitoring immune function using molecular imaging could significantly impact the diagnosis and treatment evaluation of immunological disorders and therapeutic immune responses. Positron Emission Tomography (PET) is a molecular imaging modality with applications in cancer and other diseases. PET studies of immune function have been limited by a lack of specialized probes. We identified [18F]FAC (1-(2′-deoxy-2′-[18F]fluoroarabinofuranosyl) cytosine) by differential screening as a new PET probe for the deoxyribonucleotide salvage pathway. [18F]FAC enabled visualization of lymphoid organs and was sensitive to localized immune activation in a mouse model of anti-tumor immunity. [18F]FAC microPET also detected early changes in lymphoid mass in systemic autoimmunity and allowed evaluation of immunosuppressive therapy. These data support the use of [18F]FAC PET for immune monitoring and suggest a wide range of clinical applications in immune disorders and in certain types of cancer.
FAC (1-(2-deoxy-2-[18F]fluoroarabinofuranosyl) cytosine); deoxyribonucleotide salvage pathway; PET; T lymphocytes; autoimmunity; cancer
Positron emission tomography (PET) is used in the clinic and in vivo small animal research to study molecular processes associated with diseases such as cancer, heart disease, and neurological disorders, and to guide the discovery and development of new treatments. This paper reviews current challenges of advancing PET technology and some of newly developed PET detectors and systems. The paper focuses on four aspects of PET instrumentation: high photon detection sensitivity; improved spatial resolution; depth-of-interaction (DOI) resolution and time-of-flight (TOF). Improved system geometry, novel non-scintillator based detectors, and tapered scintillation crystal arrays are able to enhance the photon detection sensitivity of a PET system. Several challenges for achieving high resolution with standard scintillator-based PET detectors are discussed. Novel detectors with 3-D positioning capability have great potential to be deployed in PET for achieving spatial resolution better than 1 mm, such as cadmium-zinc-telluride (CZT) and position-sensitive avalanche photodiodes (PSAPDs). DOI capability enables a PET system to mitigate parallax error and achieve uniform spatial resolution across the field-of-view (FOV). Six common DOI designs, as well as advantages and limitations of each design, are discussed. The availability of fast scintillation crystals such as LaBr3, and the silicon photomultiplier (SiPM) greatly advances TOF-PET development. Recent instrumentation and initial results of clinical trials are briefly presented. If successful, these technology advances, together with new probe molecules, will substantially enhance the molecular sensitivity of PET and thus increase its role in preclinical and clinical research as well as evaluating and managing disease in the clinic.
Positron Emission Tomography (PET); Photon Sensitivity; Spatial Resolution; Scintillation Detector; Semiconductor Detector; Depth-of-Interaction (DOI); Time-of-Flight (TOF)
Biomedical imaging techniques such as skeletal survey and 18F-fluorodeoxyglucose (FDG)/Positron Emission Tomography (PET) are frequently used to diagnose and stage multiple myeloma (MM) patients. However, skeletal survey has limited sensitivity as it can detect osteolytic lesions only after 30–50% cortical bone destruction, and FDG is a marker of cell metabolism that has limited sensitivity for intramedullary lesions in MM. Targeted, and non-invasive novel probes are needed to sensitively and selectively image the unique molecular signatures and cellular processes associated with MM. Very late antigen-4 (VLA-4; also called α4β1 integrin) is over-expressed on MM cells, and is one of the key mediators of myeloma cell adhesion to the bone marrow (BM) that promotes MM cell trafficking and drug resistance. Here we describe a proof-of-principle, novel molecular imaging strategy for MM tumors using a VLA-4 targeted PET radiopharmaceutical, 64Cu-CB-TE1A1P-LLP2A. Cell uptake studies in a VLA-4-positive murine MM cell line, 5TGM1, demonstrated receptor specific uptake (P<0.0001, block vs. non-block). Tissue biodistribution at 2 h of 64Cu-CB-TE1A1P-LLP2A in 5TGM1 tumor bearing syngeneic KaLwRij mice demonstrated high radiotracer uptake in the tumor (12±4.5%ID/g), and in the VLA-4 rich organs, spleen (8.8±1.0%ID/g) and marrow (11.6±2.0%ID/g). Small animal PET/CT imaging with 64Cu-CB-TE1A1P-LLP2A demonstrated high uptake in the 5TGM1 tumors (SUV 6.6±1.1). There was a 3-fold reduction in the in vivo tumor uptake in the presence of blocking agent (2.3±0.4). Additionally, 64Cu-CB-TE1A1P-LLP2A demonstrated high binding to the human MM cell line RPMI-8226 that was significantly reduced in the presence of the cold targeting agent. These results provide pre-clinical evidence that VLA-4-targeted imaging using 64Cu-CB-TE1A1P-LLP2A is a novel approach to imaging MM tumors.
Alzheimer disease (AD) is an increasingly prevalent neurodegenerative condition and a looming socioeconomic threat. A biomarker for the disease could make the process of diagnosis easier and more accurate, and accelerate drug discovery. The current work describes a method for scoring brain images that is inspired by fundamental principles from information retrieval (IR), a branch of computer science that includes the development of Internet search engines. For this research, a dataset of 254 baseline 18-F fluorodeoxyglucose positron emission tomography (FDG-PET) scans was obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). For a given contrast, a subset of scans (nine of every 10) was used to compute a residual vector that typified the difference, at each voxel, between the two groups being contrasted. Scans that were not used for computing the residual vector (the remaining one of 10 scans) were then compared to the residual vector using a cosine similarity metric. This process was repeated sequentially, each time generating cosine similarity scores on 10% of the FDG-PET scans for each contrast. Statistical analysis revealed that the scores were significant predictors of functional decline as measured by the Functional Activities Questionnaire (FAQ). When logistic regression models that incorporated these scores were evaluated with leave-one-out cross-validation, cognitively normal controls were discerned from AD with sensitivity and specificity of 94.4% and 84.8%, respectively. Patients who converted from mild cognitive impairment (MCI) to AD were discerned from MCI nonconverters with sensitivity and specificity of 89.7% and 62.9%, respectively, when FAQ scores were brought into the model. Residual vectors are easy to compute and provide a simple method for scoring the similarity between an FDG-PET scan and sets of examples from a given diagnostic group. The method is readily generalizable to any imaging modality. Further interdisciplinary work between IR and clinical neuroscience is warranted.
ADNI; Alzheimer disease; Bioinformatics; Mild cognitive impairment; PET scan
Novel anticancer drugs targeting key apoptosis regulators have been developed and are undergoing clinical trials. Pharmacodynamic biomarkers to define the optimum dose of drug that provokes tumor apoptosis are in demand; acquisition of longitudinal tumor biopsies is a significant challenge and minimally invasive biomarkers are required. Considering this, we have developed and validated a preclinical ‘death-switch' model for the discovery of secreted biomarkers of tumour apoptosis using in vitro proteomics and in vivo evaluation of the novel imaging probe [18F]ML-10 for non-invasive detection of apoptosis using positron emission tomography (PET). The ‘death-switch' is a constitutively active mutant caspase-3 that is robustly induced by doxycycline to drive synchronous apoptosis in human colorectal cancer cells in vitro or grown as tumor xenografts. Death-switch induction caused caspase-dependent apoptosis between 3 and 24 hours in vitro and regression of ‘death-switched' xenografts occurred within 24 h correlating with the percentage of apoptotic cells in tumor and levels of an established cell death biomarker (cleaved cytokeratin-18) in the blood. We sought to define secreted biomarkers of tumor apoptosis from cultured cells using Discovery Isobaric Tag proteomics, which may provide candidates to validate in blood. Early after caspase-3 activation, levels of normally secreted proteins were decreased (e.g. Gelsolin and Midkine) and proteins including CD44 and High Mobility Group protein B1 (HMGB1) that were released into cell culture media in vitro were also identified in the bloodstream of mice bearing death-switched tumors. We also exemplify the utility of the death-switch model for the validation of apoptotic imaging probes using [18F]ML-10, a PET tracer currently in clinical trials. Results showed increased tracer uptake of [18F]ML-10 in tumours undergoing apoptosis, compared with matched tumour controls imaged in the same animal. Overall, the death-switch model represents a robust and versatile tool for the discovery and validation of apoptosis biomarkers.
biomarkers; apoptosis; capase-3; death-switch; proteomics; imaging
With many desirable properties such as ease of synthesis, small size, lack of immunogenicity, and versatile chemistry, aptamers represent a class of targeting ligands that possess tremendous potential in molecular imaging applications. Non-invasive imaging of various disease markers with aptamer-based probes has many potential clinical applications such as lesion detection, patient stratification, treatment monitoring, etc. In this review, we will summarize the current status of molecular imaging with aptamer-based probes. First, fluorescence imaging will be described which include both direct targeting and activatable probes. Next, we discuss molecular magnetic resonance imaging and targeted ultrasound investigations using aptamer-based agents. Radionuclide-based imaging techniques (single-photon emission computed tomography and positron emission tomography) will be summarized as well. In addition, aptamers have also been labeled with various tags for computed tomography, surface plasmon resonance, dark-field light scattering microscopy, transmission electron microscopy, and surface-enhanced Raman spectroscopy imaging. Among all molecular imaging modalities, no single modality is perfect and sufficient to obtain all the necessary information for a particular question. Thus, a multimodality probe has also been constructed for concurrent fluorescence, gamma camera, and magnetic resonance imaging in vivo. Although the future of aptamer-based molecular imaging is becoming increasingly bright and many proof-of-principle studies have already been reported, much future effort needs to be directed towards the development of clinically translatable aptamer-based imaging agents which will eventually benefit patients.
Aptamers; molecular imaging; cancer; positron emission tomography; DNA/RNA; fluorescence; personalized medicine
The acronym THERANOSTICS epitomizes the inseparability of diagnosis and therapy, the pillars of medicine and takes into account personalized management of disease for a specific patient. Molecular phenotypes of neoplasms can be determined by molecular imaging with specific probes using positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), or optical methods, so that the treatment is specifically targeted against the tumor and its environment. To meet these demands, we need to define the targets, ligands, coupling and labeling chemistry, the most appropriate radionuclides, biodistribution modifiers, and finally select the right patients for the personalized treatment. THERANOSTICS of neuroendocrine tumors (NETs) using Ga-68 labeled tracers for diagnostics with positron emission tomography/ computed tomography (PET/CT), and using Lu-177 or other metallic radionuclides for radionuclide therapy by applying the same peptide proves that personalized radionuclide therapy today is already a fact and not a fiction.
THERANOSTICS; molecular imaging; personalized radionuclide therapy.
Destruction or changes associated with myelin membranes in the CNS play a key role in the pathogenesis of multiple sclerosis and other related neurodegenerative disorders. A long-standing goal has been to detect and quantify myelin content in vivo. For this reason, we have developed a myelin-imaging technique based on positron emission tomography (PET). PET is a quantitative imaging modality that has been widely used in clinical settings for direct assessment of biological processes at the molecular level. However, lack of myelin-imaging probes has hampered the use of PET for imaging of myelination in the CNS. Here, we report a myelin-imaging agent, termed Case Imaging Compound (CIC) that readily penetrates the blood– brain barrier and preferentially localizes to myelinated regions of the brain. After radiolabeling with positron-emitting carbon-11, [11C]CIC–PET was conducted in longitudinal studies using a lysolethicin-induced rat model of focal demyelination and subsequent remyelination. Quantitative analysis showed that the retention of [11C]CIC correlates with the level of demyelination/remyelination. These studies indicate that, for the first time, [11C]CIC–PET can be used as an imaging marker of myelination, which has the potential to be translated into clinical studies in multiple sclerosis and other myelin-related diseases for early diagnosis, subtyping, and efficacy evaluation of therapeutic treatments aimed at myelin repair.
In vivo molecular imaging has a great potential to impact medicine by detecting diseases in early stages (screening), identifying extent of disease, selecting disease- and patient-specific therapeutic treatment (personalized medicine), applying a directed or targeted therapy, and measuring molecular-specific effects of treatment. Current clinical molecular imaging approaches primarily use PET- or SPECT-based techniques. In ongoing preclinical research novel molecular targets of different diseases are identified and, sophisticated and multifunctional contrast agents for imaging these molecular targets are developed along with new technologies and instrumentation for multimodality molecular imaging. Contrast-enhanced molecular ultrasound with molecularly-targeted contrast microbubbles is explored as a clinically translatable molecular imaging strategy for screening, diagnosing, and monitoring diseases at the molecular level. Optical imaging with fluorescent molecular probes and ultrasound imaging with molecularly-targeted microbubbles are attractive strategies since they provide real-time imaging, are relatively inexpensive, produce images with high spatial resolution, and do not involve exposure to ionizing irradiation. Raman spectroscopy/microscopy has emerged as a molecular optical imaging strategy for ultrasensitive detection of multiple biomolecules/biochemicals with both in vivo and ex vivo versatility. Photoacoustic imaging is a hybrid of optical and ultrasound modalities involving optically-excitable molecularly-targeted contrast agents and quantitative detection of resulting oscillatory contrast agent movement with ultrasound. Current preclinical findings and advances in instrumentation such as endoscopes and microcatheters suggest that these molecular imaging modalities have numerous clinical applications and will be translated into clinical use in the near future.
Preclinical and clinical tomographic imaging systems increasingly are being utilized for non-invasive imaging of reporter gene products to reveal the distribution of molecular therapeutics within living subjects. Reporter gene and probe combinations can be employed to monitor vectors for gene, viral, and cell-based therapies. There are several reporter systems available; however, those employing radionuclides for positron emission tomography (PET) or singlephoton emission computed tomography (SPECT) offer the highest sensitivity and the greatest promise for deep tissue imaging in humans. Within the category of radionuclide reporters, the thyroidal sodium iodide symporter (NIS) has emerged as one of the most promising for preclinical and translational research. NIS has been incorporated into a remarkable variety of viral and non-viral vectors in which its functionality is conveniently determined by in vitro iodide uptake assays prior to live animal imaging. This review on the NIS reporter will focus on 1) differences between endogenous NIS and heterologously-expressed NIS, 2) qualitative or comparative use of NIS as an imaging reporter in preclinical and translational gene therapy, oncolytic viral therapy, and cell trafficking research, and 3) use of NIS as an absolute quantitative reporter.
Gene therapy; imaging; NIS; oncolytic virus; PET; reporter gene; SPECT; sodium iodide symporter.
Image guided technique is playing an increasingly important role in the investigation of the biodistribution and pharmacokinetics of drugs or drug delivery systems in various diseases, especially cancers. Besides anatomical imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), molecular imaging strategy including optical imaging, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) will facilitate the localization and quantization of radioisotope or optical probe labeled nanoparticle delivery systems in the category of theranostics. The quantitative measurement of the bio-distribution and pharmacokinetics of theranostics in the fields of new drug/probe development, diagnosis and treatment process monitoring as well as tracking the brain-blood-barrier (BBB) breaking through by high sensitive imaging method, and the applications of the representative imaging modalities are summarized in this review.
Image; biodistribution; pharmacokinetic; theranostics; nanoparticles; antibody.
Molecular imaging is a rapidly emerging research tool and clinical discipline aimed at noninvasive, quantitative visualization of in vivo molecular processes occurring at cellular and subcellular levels. At present, advancement of the molecular imaging field is driven by the development of improved imaging hardware for use in preclinical and clinical settings, the identification and validation of new, biologically relevant imaging targets, and the development of improved imaging probes derived from novel chemistries. Of these 3 essential facets, which comprise a majority of current molecular imaging research, hardware development and novel target discovery significantly outpace the development and clinical advancement of new molecular imaging probes, particularly with respect to cancer imaging.
molecular imaging; imaging probe discovery; HTS
Molecular imaging is devoted to the discovery and application of specific biological imaging approaches that complement traditional anatomical imaging. This field continues to witness impressive growth, particularly in the study of oncology, neurology, and cardiovascular disease (CVD). Interest in molecular imaging technologies stems from its great potential, not only to heighten our understanding and diagnostic capability of common CVD scenarios, but also to offer the prospect of personalized treatment and early monitoring of therapeutic response. Targeted imaging reporters are now spawning the development of combined diagnostic and therapeutic agents that can deliver therapy to individual cells in affected tissues. Recently, diagnostic imaging probes for myocardial infarction (MI), stem cell tracking, and atherosclerotic vascular disease have demonstrated significant advances in preclinical research and development (also see the Online Appendix). Clinical molecular imaging studies have further expanded into the areas of aortic dissection and aneurysm disease, and have provided new insights into aspects of heart failure and transplant medicine. In this review, we highlight outstanding CVD molecular imaging studies published over the past year. A summary of important clinical and preclinical imaging agents and applications is provided in Table 1.
atherosclerosis; heart failure; molecular imaging; myocardial infarction; thrombosis
In vivo detection of Alzheimer's disease (AD) neuropathology in living patients using positron emission tomography (PET) in conjunction with high affinity molecular imaging probes for β-amyloid (Aβ) and tau has the potential to assist with early diagnosis, evaluation of disease progression, and assessment of therapeutic interventions. Animal models of AD are valuable for exploring the in vivo binding of these probes, particularly their selectivity for specific neuropathologies, but prior PET experiments in transgenic mice have yielded conflicting results. In this work, we utilized microPET imaging in a transgenic rat model of brain Aβ deposition to assess [F-18]FDDNP binding profiles in relation to age-associated accumulation of neuropathology. Cross-sectional and longitudinal imaging demonstrated that [F-18]FDDNP binding in the hippocampus and frontal cortex progressively increases from 9 to 18 months of age and parallels age-associated Aβ accumulation. Specificity of in vivo [F-18]FDDNP binding was assessed by naproxen pretreatment, which reversibly blocked [F-18]FDDNP binding to Aβ aggregrates. Both [F-18]FDDNP microPET imaging and neuropathological analyses revealed decreased Aβ burden after intracranial anti-Aβ antibody administration. The combination of this non-invasive imaging method and robust animal model of brain Aβ accumulation allows for future longitudinal in vivo assessments of potential therapeutics for AD that target Aβ production, aggregation, and/or clearance. These results corroborate previous analyses of [F-18]FDDNP PET imaging in clinical populations.
[F-18]FDDNP; positron emission tomography; amyloid; transgenic rat; naproxen; immunotherapy
Molecular imaging employs molecularly targeted probes to visualize and often quantify distinct disease-specific markers and pathways. Modalities like intravital confocal or multiphoton microscopy, near-infrared fluorescence combined with endoscopy, surface reflectance imaging, or fluorescence-mediated tomography, and radionuclide imaging with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are increasingly used for small animal high-throughput screening, drug development and testing, and monitoring gene therapy experiments. In the clinical treatment of breast cancer, PET and SPECT as well as magnetic resonance-based molecular imaging are already established for the staging of distant disease and intrathoracic nodal status, for patient selection regarding receptor-directed treatments, and to gain early information about treatment efficacy. In the near future, reporter gene imaging during gene therapy and further spatial and qualitative characterization of the disease can become clinically possible with radionuclide and optical methods. Ultimately, it may be expected that every level of breast cancer treatment will be affected by molecular imaging, including screening.
Breast cancer; Molecular imaging; PET; MRI; Optical imaging; Receptor
Parallel to the advances in diagnostic imaging using positron emission tomography (PET), and availability of new systemic treatment options, the treatment paradigm in oncology has shifted towards more aggressive therapeutic interventions to include cytoreductive techniques and metastasectomies. Intraoperative localization of PET positive recurrent/metastatic lesions can be facilitated using a hand-held PET probe.
Materials and methods
Records of patients who underwent PET probe-guided surgery were reviewed. Surgical indications and operative targets were determined based on diagnostic PET/PET-CT images performed prior to probe-guided surgical planning. PET probe-guided surgery was performed on a separate day using a high-energy gamma probe (PET probe, Care Wise Medical, Morgan Hills CA) 2–6 hours post-injection of 5–15 mCi FDG. Probe count rates, target-to-background ratios, and lesion detection success were analyzed.
Twenty-four patients underwent PET probe-guided surgery; one patient had two PET-probe guided surgeries resulting in a total of 25 cases (5 colorectal cancer cases, 4 thyroid cancer cases, 6 lymphoma cancer cases, and 10 other cancer cases). Surgical indication was diagnostic exploration in 6 cases with lymphoma and 1 case with head and neck cancer (28%). The remaining 18 cases (72%) underwent PET probe-guided surgery with a therapeutic intent in a recurrent or metastatic disease setting. All the lesions identified and targeted on a preoperative FDG-PET scan were detected by the PET probe with satisfactory in-vivo lesion count rates and a TBR of ≥ 1.5. PET probe allowed localization of lesions that were non-palpable and non-obvious at surgical exploration in 8 patients.
The use of the PET probe improves the success of surgical exploration in selected indications. Separate day protocol is clinically feasible allowing for flexible operating room scheduling.
Positron emission tomography (PET) is a non-invasive molecular imaging technique using positron-emitting radioisotopes to study functional processes within the body. High resolution PET scanners designed for imaging rodents and non-human primates are now commonplace in preclinical research. Brain imaging in this context, with motion compensation, can potentially enhance the usefulness of PET by avoiding confounds due to anaesthetic drugs and enabling freely moving animals to be imaged during normal and evoked behaviours. Due to the frequent and rapid motion exhibited by alert, awake animals, optimal motion correction requires frequently sampled pose information and precise synchronisation of these data with events in the PET coincidence data stream. Motion measurements should also be as accurate as possible to avoid degrading the excellent spatial resolution provided by state-of-the-art scanners. Here we describe and validate methods for optimised motion tracking suited to the correction of motion in awake rats. A hardware based synchronisation approach is used to achieve temporal alignment of tracker and scanner data to within 10 ms. We explored the impact of motion tracker synchronisation error, pose sampling rate, rate of motion, and marker size on motion correction accuracy. With accurate synchronisation (<100 ms error), a sampling rate of >20 Hz, and a small head marker suitable for awake animal studies, excellent motion correction results were obtained in phantom studies with a variety of continuous motion patterns, including realistic rat motion (<5% bias in mean concentration). Feasibility of the approach was also demonstrated in an awake rat study. We conclude that motion tracking parameters needed for effective motion correction in preclinical brain imaging of awake rats are achievable in the laboratory setting. This could broaden the scope of animal experiments currently possible with PET.
The Open Drug Discovery Teams (ODDT) project provides a mobile app primarily intended as a research topic aggregator of predominantly open science data collected from various sources on the internet. It exists to facilitate interdisciplinary teamwork and to relieve the user from data overload, delivering access to information that is highly relevant and focused on their topic areas of interest. Research topics include areas of chemistry and adjacent molecule-oriented biomedical sciences, with an emphasis on those which are most amenable to open research at present. These include rare and neglected diseases, and precompetitive and public-good initiatives such as green chemistry. The ODDT project uses a free mobile app as user entry point. The app has a magazine-like interface, and server-side infrastructure for hosting chemistry-related data as well as value added services. The project is open to participation from anyone and provides the ability for users to make annotations and assertions, thereby contributing to the collective value of the data to the engaged community. Much of the content is derived from public sources, but the platform is also amenable to commercial data input. The technology could also be readily used in-house by organizations as a research aggregator that could integrate internal and external science and discussion. The infrastructure for the app is currently based upon the Twitter API as a useful proof of concept for a real time source of publicly generated content. This could be extended further by accessing other APIs providing news and data feeds of relevance to a particular area of interest. As the project evolves, social networking features will be developed for organizing participants into teams, with various forms of communication and content management possible.
Apps; Chemistry; Cloud computing; Collaboration; Green chemistry; Mobile chemistry; Open data; Open science; Open source drug discovery; Web services
The overall objectives of this research are to (i) develop azulene-based positron emission tomography (PET) probes and (ii) image COX2 as a potential biomarker of breast cancer. Several lines of research have demonstrated that COX2 is overexpressed in breast cancer and that its presence correlates with poor prognoses. While other studies have reported that COX2 inhibition can be modulated and used beneficially as a chemopreventive strategy in cancer, no viable mechanism for achieving that approach has yet been developed. This shortfall could be circumvented through in vivo imaging of COX2 activity, particularly using sensitive imaging techniques such as PET. Toward that goal, our laboratory focuses on the development of novel 18F-labled COX2 probes. We began the synthesis of the probes by transforming tropolone into a lactone, which was subjected to an [8 + 2] cycloaddition reaction to yield 2-methylazulene as the core ring of the probe. After exploring numerous synthetic routes, the final target molecule and precursor PET compounds were prepared successfully using convergent synthesis. Conventional 18F labeling methods caused precursor decomposition, which prompted us to hypothesize that the acidic protons of the methylene moiety between the azulene and thiazole rings were readily abstracted by a strong base such as potassium carbonate. Ultimately, this caused the precursors to disintegrate. This observation was supported after successfully using an 18F labeling strategy that employed a much milder phosphate buffer. The 18F-labeled COX2 probe was tested in a breast cancer xenograft mouse model. The data obtained via successive whole-body PET/CT scans indicated probe accumulation and retention in the tumor. Overall, the probe was stable in vivo and no defluorination was observed. A biodistribution study and Western blot analysis corroborate with the imaging data. In conclusion, this novel COX2 PET probe was shown to be a promising agent for cancer imaging and deserves further investigation.
azulene; COX2; breast cancer; PET; CT; convergence synthesis; molecular imaging
Molecular imaging aims towards the non-invasive characterization of disease-specific molecular alterations in the living organism in vivo. In that, molecular imaging opens a new dimension in our understanding of disease pathogenesis, as it allows the non-invasive determination of the dynamics of changes on the molecular level.
Imaging of AD characteristic changes by μPET
The imaging technology being employed includes magnetic resonance imaging (MRI) and nuclear imaging as well as optical-based imaging technologies. These imaging modalities are employed together or alone for disease phenotyping, development of imaging-guided therapeutic strategies and in basic and translational research.
In this study, we review recent investigations employing positron emission tomography and MRI for phenotyping mouse models of Alzheimers’ disease by imaging. We demonstrate that imaging has an important role in the characterization of mouse models of neurodegenerative diseases.
Molecular imaging; μPET; Mouse models; AD
Metabotropic glutamate receptors (mGluRs) belong to a family of G-protein coupled receptors involved in the modulation of fast excitatory transmission. In particular, the subtype-5 receptor (mGluR5) was found to be an attractive target for the treatment and diagnosis of variety of psychiatric and neurological disease including anxiety, depression, epilepsy, drug addiction, and Parkinson's disease. Positron emission tomography (PET) is a highly sensitive imaging technique that holds great potential for the diagnosis of a brain disorder. In the study published in the American Journal of Nuclear Medicine and Molecular Imaging, a 18F labelled PET probe was developed targeting mGluR5. This paper represents the efforts and challenges on the design and development of novel PET tracers for mGluR5 imaging.
mGluR5; positron emission tomography (PET); 18F; 11C; molecular imaging
Most patients with epithelial ovarian cancer (EOC) experience drug-resistant disease recurrence. Identification of new treatments is a high priority, and preclinical studies in mouse models of EOC may expedite this goal. We previously developed methods for magnetic resonance imaging (MRI) for tumor detection and quantification in a transgenic mouse model of EOC. The goal of this study was to determine whether three-dimensional (3D) fluorescence molecular tomography (FMT) and fluorescent molecular imaging probes could be effectively used for in vivo detection of ovarian tumors and response to therapy. Ovarian tumor-bearing TgMISIIR-TAg mice injected with fluorescent probes were subjected to MRI and FMT. Tumor-specific probe retention was identified in vivo by alignment of the 3D data sets, confirmed by ex vivo fluorescent imaging and correlated with histopathologic findings. Mice were treated with standard chemotherapy, and changes in fluorescent probe binding were detected by MRI and FMT. Ovarian tumors were detected using probes specific for cathepsin proteases, matrix metalloproteinases (MMPs), and integrin αvβ3. Cathepsin and integrin αvβ3 probe activation and retention correlated strongly with tumor volume. MMP probe activation was readily detected in tumors but correlated less strongly with tumor volume. Tumor regression associated with response to therapy was detected and quantified by serial MRI and FMT. These results demonstrate the feasibility and sensitivity of FMT for detection and quantification of tumor-associated biologic targets in ovarian tumors and support the translational utility of molecular imaging to assess functional response to therapy in mouse models of EOC.