Translational Molecular Imaging Research Articles

Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development.

Cholesterol homeostasis is impaired in Alzheimer's disease; however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date. Several recent milestone developments have substantially improved our understanding of how excess neuronal cholesterol contributes to the pathophysiology of Alzheimer's disease. Indeed, neuronal cholesterol was linked to the formation of amyloid-β and neurofibrillary tangles through molecular pathways that were recently delineated in mechanistic studies. Furthermore, remarkable advances in translational molecular imaging have now made it possible to probe cholesterol metabolism in the living human brain with PET, which is an important prerequisite for future clinical trials that target the brain cholesterol machinery in Alzheimer's disease patients-with the ultimate aim being to develop disease-modifying treatments. This work summarizes current concepts of how the biosynthesis, transport and clearance of brain cholesterol are affected in Alzheimer's disease. Further, current strategies to reverse these alterations by pharmacotherapy are critically discussed in the wake of emerging translational research tools that support the assessment of brain cholesterol biology not only in animal models but also in patients with Alzheimer's disease.

Visualizing reactive astrocytes: Positron emission tomography imaging ligands for imidazoline‐2 binding sites

AbstractImidazoline‐2 binding sites (I2BS) exhibit specific expression in reactive astrocytes of the brain and are implicated in various pathophysiological processes, including analgesia, inflammation, Alzheimer's disease, Parkinson's disease, and glial tumors. However, the lack of available protein structural data poses a challenge in the exploration of I2BS functions and pharmacological characterizations, indicating the need for the discovery of selective ligands. As a non‐invasive and translational molecular imaging tool, positron emission tomography (PET) has found wide application in clinical diagnosis and drug discovery. Consequently, several PET ligands have been developed to “visualize” I2BS in the living brain, thereby elucidating the biological implications of I2BS and facilitating I2BS‐directed drug development. This review offers a comprehensive update on I2BS PET ligands, with a focus on their chemotypes and PET imaging outcomes. Furthermore, the review provides a summary of recent I2BS drug discoveries, which could serve as a catalyst for the development of more potent PET ligands.

Recent Trends in Diagnostic Biomarkers of Tumor Microenvironment.

The tumor microenvironment (TME) play critical roles in tumor survival, progression, and metastasis and can be considered potential targets for molecular imaging of cancer. The targeting agents for imaging of TME components (e.g., fibroblasts, mesenchymal stromal cells, immune cells, extracellular matrix, blood vessels) provide a promising strategy to target these biomarkers for the early diagnosis of cancers. Moreover, various cancer types have similar tumor immune microenvironment (TIME) features that targeting those biomarkers and offer clinically translatable molecular imaging of cancers. In this review, we categorize and summarize the components in TME which have been targeted for molecular imaging. Moreover, this review updated the recent progress in targeted imaging of TIME biological molecules by various modalities for the early detection of cancer.

Translational Molecular Imaging Tool of Vulnerable Carotid Plaque: Evaluate Effects of Statin Therapy on Plaque Inflammation and American Heart Association–Defined Risk Levels in Cuff-Implanted Apolipoprotein E–Deficient Mice

Identification of high-risk carotid plaques in asymptomatic patients remains a challenging but crucial step in stroke prevention. The challenge is to accurately monitor the development of high-risk carotid plaques and promptly identify patients, who are unresponsive to best medical therapy, and hence targeted for carotid surgical interventions to prevent stroke. Inflammation is a key operator in destabilisation of plaques prior to clinical sequelae. Currently, there is a lack of imaging tool in routine clinical practice, which allows assessment of inflammatory activity within the atherosclerotic plaque. Herein, we have used a periarterial cuff to generate a progressive carotid atherosclerosis model in apolipoprotein E–deficient mice. This model produced clinically relevant plaques with different levels of risk, fulfilling American Heart Association (AHA) classification, at specific timepoints and locations, along the same carotid artery. Exploiting this platform, we have developed smart molecular magnetic resonance imaging (MRI) probes consisting of dual-targeted microparticles of iron oxide (DT-MPIO) against VCAM-1 and P-selectin, to evaluate the anti-inflammatory effect of statin therapy on progressive carotid atherosclerosis. We demonstrated that in vivo DT-MPIO-enhanced MRI can (i) quantitatively track plaque inflammation from early to advanced stage; (ii) identify and characterise high-risk inflamed, vulnerable plaques; and (iii) monitor the response to statin therapy longitudinally. Moreover, this molecular imaging–defined therapeutic response was validated using AHA classification of human plaques, a clinically relevant parameter, approximating the clinical translation of this tool. Further development and translation of this molecular imaging tool into the clinical arena may potentially facilitate more accurate risk stratification, permitting timely identification of the high-risk patients for prophylactic carotid intervention, affording early opportunities for stroke prevention in the future.

Abstract 13560: System Gene Regulatory Network-Based Drug Repurposing Combined With Preclinical Molecular Imaging Identifies Anti-Atherosclerotic Properties of Auranofin

Introduction: The identification of new treatments for atherosclerosis (ACVD), a common complex disease, is a daunting task because sets of genes, rather than individual genes, control cell functions. Using systems genetics, our team identified gene regulatory network (GRN42) that is active in the human atherosclerotic arterial wall and is involved in the regulation of foam cell formation. Hypothesis: A network-driven drug repurposing approach combined with rigorous preclinical validation will identify new uses for existing drugs to treat ACVD. Methods: We developed a GRN42-based computational drug repurposing pipeline to infer new uses for existing drugs. Selected compounds were screened by measuring their ability to inhibit foam cell formation in vitro using THP-1-derived macrophages. The in vivo efficacy was validated in ApoE-/- mice fed a western diet by histology and in atherosclerotic rabbits using histology and non-invasive 18 F-FDG PET-MR imaging. Results: 30 candidate compounds were predicted to influence the function of GRN42 and 5 were selected for in vitro screening based on their prediction scores (Figure 1A). As expected, vitamin D reduced cholesteryl esters accumulation in foam cells. Auranofin, and FDA-approved drug for rheumatoid arthritis reduced foam cell formation. As predicted methyl-fasudil had no effect, while nicardipine and flutamide increased foam cell formation (Figure 1B). Auranofin reduced plaque burden in ApoE-/- mice (Figure 1C) and in rabbits reduced lipid accumulation (Figure 1D) and inflammation shown as reduced 18 F-FDG uptake in the arterial wall (Figure 1E). Conclusions: Our results provide robust evidence that a GRN-based computational drug repurposing approach, when combined with robust preclinical validation using translational molecular imaging, can successfully identify new uses of existing drugs for the treatment of ACVD.

The Repertoire of Small-Molecule PET Probes for Neuroinflammation Imaging: Challenges and Opportunities beyond TSPO.

Neuroinflammation is an adaptive response of the central nervous system to diverse potentially injurious stimuli, which is closely associated with neurodegeneration and typically characterized by activation of microglia and astrocytes. As a noninvasive and translational molecular imaging tool, positron emission tomography (PET) could provide a better understanding of neuroinflammation and its role in neurodegenerative diseases. Ligands to translator protein (TSPO), a putative marker of neuroinflammation, have been the most commonly studied in this context, but they suffer from serious limitations. Herein we present a repertoire of different structural chemotypes and novel PET ligand design for classical and emerging neuroinflammatory targets beyond TSPO. We believe that this Perspective will support multidisciplinary collaborations in academic and industrial institutions working on neuroinflammation and facilitate the progress of neuroinflammation PET probe development for clinical use.

Proof of concept of a multimodal intravital molecular imaging system for tumour transpathology investigation

BackgroundTranspathology highlights the interpretation of the underlying physiology behind molecular imaging. However, it remains challenging due to the discrepancies between in vivo and in vitro measurements and difficulties of precise co-registration between trans-scaled images. This study aims to develop a multimodal intravital molecular imaging (MIMI) system as a tool for in vivo tumour transpathology investigation.MethodsThe proposed MIMI system integrates high-resolution positron imaging, magnetic resonance imaging (MRI) and microscopic imaging on a dorsal skin window chamber on an athymic nude rat. The window chamber frame was designed to be compatible with multimodal imaging and its fiducial markers were customized for precise physical alignment among modalities. The co-registration accuracy was evaluated based on phantoms with thin catheters. For proof of concept, tumour models of the human colorectal adenocarcinoma cell line HT-29 were imaged. The tissue within the window chamber was sectioned, fixed and haematoxylin–eosin (HE) stained for comparison with multimodal in vivo imaging.ResultsThe final MIMI system had a maximum field of view (FOV) of 18 mm × 18 mm. Using the fiducial markers and the tubing phantom, the co-registration errors are 0.18 ± 0.27 mm between MRI and positron imaging, 0.19 ± 0.22 mm between positron imaging and microscopic imaging and 0.15 ± 0.27 mm between MRI and microscopic imaging. A pilot test demonstrated that the MIMI system provides an integrative visualization of the tumour anatomy, vasculatures and metabolism of the in vivo tumour microenvironment, which was consistent with ex vivo pathology.ConclusionsThe established multimodal intravital imaging system provided a co-registered in vivo platform for trans-scale and transparent investigation of the underlying pathology behind imaging, which has the potential to enhance the translation of molecular imaging.

In Vivo Platelet Detection Using a Glycoprotein IIb/IIIa-Targeted Near-Infrared Fluorescence Imaging Probe.

Platelets play a prominent role in multiple diseases, in particular arterial and venous thrombosis and also in atherosclerosis and cancer. To advance the in vivo study of the biological activity of this cell type from a basic experimental focus to a clinical focus, new translatable platelet-specific molecular imaging agents are required. Herein, we report the development of a near-infrared fluorescence probe based upon tirofiban, a clinically approved small-molecule glycoprotein IIb/IIIa inhibitor (GPIIb/IIIa). Through in vitro experiments with human platelets and in vivo ones in a murine model of deep-vein thrombosis, we demonstrate the avidity of the generated probe for activated platelets, with the added benefit of a short blood half-life, thereby enabling rapid in vivo visualization within the vasculature.

2020 RSNA Outstanding Researcher.

HomeRadiologyVol. 298, No. 1 Next CommunicationsFree AccessSpecial Communications2020 RSNA Outstanding ResearcherJames P. BorgstedeJames P. BorgstedeJames P. BorgstedePublished Online:Dec 1 2020https://doi.org/10.1148/radiol.2020209023MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In David Mankoff, MD, PhDDownload as PowerPointOpen in Image Viewer As one of the foremost authorities in nuclear medicine/PET, David Mankoff, MD, PhD, is a leader in molecular imaging science and a pioneer in the development of whole-body PET imaging.“Dr Mankoff is a true renaissance imaging specialist,” said RSNA President James P. Borgstede, MD. “He is a researcher, an inventor, an educator and a clinical specialist. All of imaging is fortunate to have Dr Mankoff as a colleague.”Dr Mankoff is the Gerd Muehllehner Professor of Radiology and vice chair of research at the University of Pennsylvania (Penn) Perelman School of Medicine and associate director of education and research at the Abramson Cancer Center, both in Philadelphia.While earning a PhD in bioengineering, Dr Mankoff worked with his thesis advisor, the late Gerd Muehllehner, PhD, to develop a commercial version of the scanner that later formed the basis for the PennPET Explorer, a whole-body PET imaging system recently developed at Penn.After earning his PhD and MD at Penn, Dr Mankoff completed his residency in internal medicine and nuclear medicine at the University of Washington in Seattle. He remained there, eventually becoming a full professor of radiology, medicine, and bioengineering.During his time in Seattle, Dr Mankoff developed research interests in translational cancer molecular imaging and quantitative PET imaging and image analysis. In 2013, he returned to Penn School of Medicine as a professor of radiology and the PET Center director.A leading researcher with a particular interest in breast cancer, Dr Mankoff has maintained more than 20 years of continuous funding from federal sources and has been recognized as a Susan G. Komen Scholar since 2012.Key research achievements include defining applications of FDG PET to breast cancer staging and response evaluation, translating novel tracers to early human trials, studying the in vivo biology of cancer metabolism, and imaging estrogen receptor expression in breast cancer using PET.At the national level, Dr Mankoff has served as a committee leader and scientific planning co-chair of the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network (ECOG-ACRIN). He is a former steering committee chair of the NCI Quantitative Imaging Executive Committee, former member of the NCI Clinical Trials Advisory Committee, and former past president of the American Board of Nuclear Medicine.Dr Mankoff is associate editor for RSNA’s newest journal, Radiology: Imaging Cancer. He also serves on the editorial boards of several scientific journals. Dr Mankoff is co-chair of the RSNA Vice Chairs of Research Group and a member of the RSNA Committee on Scientific Affairs. He has also been active in the RSNA Clinical Trial Methodology Workshop and he has served as workshop co-director.Recognized for his many contributions to the field, Dr Mankoff was named an RSNA Honored Educator in 2013, 2018, and 2019. He received the Distinguished Investigator Award from the Academy of Radiology Research in 2018.Article HistoryPublished online: Dec 01 2020Published in print: Jan 2021 FiguresReferencesRelatedDetailsRecommended Articles Linda Moy, MD, Named New Editor of RadiologyRadioGraphics2022Volume: 42Issue: 2pp. E37-E38Linda Moy, MD, Named New Editor of RadiologyRadiology2022Volume: 303Issue: 1pp. 3-4PET Molecular Imaging as a Tool for Precision OncologyRadiology2020Volume: 296Issue: 2pp. 379-380Bruce G. Haffty, MD, President, Radiological Society of North America, 2022Radiology2022Volume: 302Issue: 3pp. 492-493Mutation Profiles of Urothelial Cancer: Will Genomics Change Radiology or Vice Versa?Radiology2020Volume: 295Issue: 3pp. 581-582See More RSNA Education Exhibits Breast Cancer in Younger Women: Screening and Diagnostic Imaging ExaminationsDigital Posters2018Non-BRCA Early Onset Breast Cancer in Young Women: Challenges and OpportunitiesDigital Posters2020Assessing Immunotherapy with Functional and Molecular Imaging and Radiomics: Whence and WitherDigital Posters2019 RSNA Case Collection Occult Breast CancerRSNA Case Collection2022Inflammatory breast cancerRSNA Case Collection2020Primary breast lymphomaRSNA Case Collection2020 Vol. 298, No. 1 Metrics Altmetric Score PDF download

Development of a Translatable Ultrasound Molecular Imaging Agent for Inflammation

This study details the development, characterization and non-clinical efficacy of an ultrasound molecular imaging agent intended for molecular imaging of P-selectin in humans. A targeting ligand based on a recently discovered human selectin ligand was manufactured as fusion protein, and activity for human and mouse P- and E-selectin was evaluated by functional immunoassay. The targeting ligand was covalently conjugated to a lipophilic anchor inserted into a phospholipid microbubble shell. Three lots of the targeted microbubble drug product, TS-07-009, were produced, and assays for size distribution, zeta potential and morphology were established. The suitability of TS-07-009 as a molecular imaging agent was evaluated in vitro in a flow-based adhesion assay and in vivo using a canine model of transient myocardial ischemia. Selectivity for P-selectin over E-selectin was observed in both the human and murine systems. Contrast agent adhesion increased with P-selectin concentration in a dynamic adhesion assay. Significant contrast enhancement was observed on ultrasound imaging with TS-07-009 in post-ischemic canine myocardium at 30 or 90 min of re-perfusion. Negligible enhancement was observed in resting (no prior ischemia) hearts or with a control microbubble 90 min after ischemia. The microbubble contrast agent described here exhibits physiochemical properties and in vivo behavior suitable for development as a clinical imaging agent.

Clinical Imaging of Choroid Plexus in Health and in Brain Disorders: A Mini-Review.

The choroid plexuses (ChPs) perform indispensable functions for the development, maintenance and functioning of the brain. Although they have gained considerable interest in the last years, their involvement in brain disorders is still largely unknown, notably because their deep location inside the brain hampers non-invasive investigations. Imaging tools have become instrumental to the diagnosis and pathophysiological study of neurological and neuropsychiatric diseases. This review summarizes the knowledge that has been gathered from the clinical imaging of ChPs in health and brain disorders not related to ChP pathologies. Results are discussed in the light of pre-clinical imaging studies. As seen in this review, to date, most clinical imaging studies of ChPs have used disease-free human subjects to demonstrate the value of different imaging biomarkers (ChP size, perfusion/permeability, glucose metabolism, inflammation), sometimes combined with the study of normal aging. Although very few studies have actually tested the value of ChP imaging biomarkers in patients with brain disorders, these pioneer studies identified ChP changes that are promising data for a better understanding and follow-up of diseases such as schizophrenia, epilepsy and Alzheimer’s disease. Imaging of immune cell trafficking at the ChPs has remained limited to pre-clinical studies so far but has the potential to be translated in patients for example using MRI coupled with the injection of iron oxide nanoparticles. Future investigations should aim at confirming and extending these findings and at developing translational molecular imaging tools for bridging the gap between basic molecular and cellular neuroscience and clinical research.

Sugar-based biopolymers as novel imaging agents for molecular magnetic resonance imaging.

Sugar-based biopolymers have been recognized as attractive materials to develop macromolecule- and nanoparticle-based cancer imaging and therapy. However, traditional biopolymer-based imaging approaches rely on the use of synthetic or isotopic labeling, and because of it, clinical translation often is hindered. Recently, a novel magnetic resonance imaging (MRI) technology, chemical exchange saturation transfer (CEST), has emerged, which allows the exploitation of sugar-based biopolymers as MRI agents by their hydroxyl protons-rich nature. In the study, we reviewed recent studies on the topic of CEST MRI detection of sugar-based biopolymers. The CEST MRI property of each biopolymer was briefly introduced, followed by the pre-clinical and clinical applications. The findings of these preliminary studies imply the enormous potential of CEST detectable sugar-based biopolymers in developing highly sensitive and translatable molecular imaging agents and constructing image-guided biopolymer-based drug delivery systems. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Ultrasound Molecular Imaging of Inflammation in Mouse Abdominal Aorta.

The aim of this study was to demonstrate a new clinically translatable ultrasound molecular imaging approach, modulated acoustic radiation force-based imaging, which is capable of rapid and reliable detection of inflammation as validated in mouse abdominal aorta. Animal studies were approved by the Institutional Animal Care and Use Committee at the University of Virginia. C57BL/6 mice stimulated with tumor necrosis factor α, or fed with a high-fat diet, were used as inflammation (MInflammation) and diet-induced obesity (DIO) (MDIO) models, respectively. C57BL/6 mice, not exposed to tumor necrosis factor α or DIO, were used as controls (MNormal). P-selectin-targeted (MBP-selectin), vascular cell adhesion molecule (VCAM)-1-targeted (MBVCAM-1), and isotype control (MBControl) microbubbles were synthesized by conjugating anti-P-selectin, anti-VCAM-1, and isotype control antibodies to microbubbles, respectively. The abdominal aortas were imaged for 180 seconds during a constant infusion of microbubbles. A parameter, residual-to-saturation ratio (RSR), was used to assess P-selectin and VCAM-1. Statistical analysis was performed with the Student t test. For the inflammation model, RSR of the MInflammation + MBP-selectin group was significantly higher (40.9%, P < 0.0005) than other groups. For the DIO model, RSR of the MDIO + MBVCAM-1 group was significantly higher (60.0%, P < 0.0005) than other groups. Immunohistochemistry staining of the abdominal aorta confirmed the expression of P-selectin and VCAM-1. A statistically significant assessment of P-selectin and VCAM-1 in mouse abdominal aorta was achieved. This technique yields progress toward rapid targeted molecular imaging in large blood vessels and thus has the potential for early diagnosis, treatment selection, and risk stratification of atherosclerosis.

Al18F-Labeling Of Heat-Sensitive Biomolecules for Positron Emission Tomography Imaging.

Positron emission tomography (PET) using radiolabeled biomolecules is a translational molecular imaging technology that is increasingly used in support of drug development. Current methods for radiolabeling biomolecules with fluorine-18 are laborious and require multistep procedures with moderate labeling yields. The Al18F-labeling strategy involves chelation in aqueous medium of aluminum mono[18F]fluoride ({Al18F}2+) by a suitable chelator conjugated to a biomolecule. However, the need for elevated temperatures (100-120 °C) required for the chelation reaction limits its widespread use. Therefore, we designed a new restrained complexing agent (RESCA) for application of the AlF strategy at room temperature.Methods. The new chelator RESCA was conjugated to three relevant biologicals and the constructs were labeled with {Al18F}2+ to evaluate the generic applicability of the one-step Al18F-RESCA-method.Results. We successfully labeled human serum albumin with excellent radiochemical yields in less than 30 minutes and confirmed in vivo stability of the Al18F-labeled protein in rats. In addition, we efficiently labeled nanobodies targeting the Kupffer cell marker CRIg, and performed µPET studies in healthy and CRIg deficient mice to demonstrate that the proposed radiolabeling method does not affect the functional integrity of the protein. Finally, an affibody targeting HER2 (PEP04314) was labeled site-specifically, and the distribution profile of (±)-[18F]AlF(RESCA)-PEP04314 in a rhesus monkey was compared with that of [18F]AlF(NOTA)-PEP04314 using whole-body PET/CT.Conclusion. This generic radiolabeling method has the potential to be a kit-based fluorine-18 labeling strategy, and could have a large impact on PET radiochemical space, potentially enabling the development of many new fluorine-18 labeled protein-based radiotracers.

A single-scan protocol for absolute D2/3 receptor quantification with [123I]IBZM SPECT

PurposeMolecular imaging of the D2/3 receptor is widely used in neuropsychiatric research. Non-displaceable binding potential (BPND) is a very popular quantitative index, defined as the product of the receptor concentration (Bavail) and the radiotracer affinity for the receptor (1/appKd). As the appKd is influenced by parameters such as the endogenous neurotransmitter dynamics, it often constitutes a confounding factor in research studies. A simplified method for absolute quantification of both these parameters would be of great interest in this context. Here, we describe the use of a partial saturation protocol that permits to produce an in vivo Scatchard plot and thus estimate Bavail and appKd separately, through a single dynamic SPECT session. To validate this approach, a multi-injection protocol is used for the full kinetic modeling of [123I]IBZM using a 3-tissue compartment, 7-parameter model (3T-7k). Finally, more “classic” BPND estimation methods are also validated against the results of the 3T-7k. MethodsTwenty-nine male rats were used. Binding parameters were estimated using the 3T-7k in a multi-injection protocol. A partial saturation protocol was applied at the region- and voxel-level and results were compared to those obtained with the 3T-7k model. The partial saturation protocol was applied after an adenovirus-mediated D2 receptor striatal overexpression and in an amphetamine-induced dopamine release paradigm. The Simplified Reference Tissue Model (SRTM), the Logan's non-invasive graphical analysis (LNIGA) and a simple standardized uptake ratio (SUR) method were equally applied. ResultsThe partial saturation experiments gave similar values as the 3T-7k both at the regional and voxel-level. After adenoviral-mediated D2-receptor overexpression, an increase in Bavail by approximately 18% was observed in the striatum. After amphetamine administration, a 16.93% decrease in Bavail (p<0.05) and a 39.12% increase (p<0.01) in appKd was observed. BPND derived from SRTM, LNIGA and SUR correlated well with the Bavail values from the 3T-7k (r=0.84, r=0.84 and r=0.83, respectively, p<0.0001 for all correlations). ConclusionA partial saturation protocol permits the non-invasive and time-efficient estimation of Bavail and appKd separately. Given the different biological phenomena that underlie these parameters, this method may be applied for the in-depth study of the dopaminergic system in translational molecular imaging studies. It can detect the biological variations in these parameters, dissociating the variations in receptor density (Bavail) from affinity (1/appKd), which reflects the interactions of the receptor with its endogenous ligand.

Ultra-Low-Dose Ultrasound Molecular Imaging for the Detection of Angiogenesis in a Mouse Murine Tumor Model: How Little Can We See?

The objective of this study was to evaluate the minimum microbubble dose for ultrasound molecular imaging to achieve statistically significant detection of angiogenesis in a mouse model. The preburst minus postburst method was implemented on a Verasonics ultrasound research scanner using a multiframe compounding pulse inversion imaging sequence. Biotinylated lipid (distearoyl phosphatidylcholine-based) microbubbles that were conjugated with antivascular endothelial growth factor 2 (VEGFR2) antibody (MBVEGFR2) or isotype control antibody (MBControl) were injected into mice carrying adenocarcinoma xenografts. Different injection doses ranging from 5 × 10 to 1 × 10 microbubbles per mouse were evaluated to determine the minimum diagnostically effective dose. The proposed imaging sequence was able to achieve statistically significant detection (P < 0.05, n = 5) of VEGFR2 in tumors with a minimum MBVEGFR2 injection dose of only 5 × 10 microbubbles per mouse (distearoyl phosphatidylcholine at 0.053 ng/g mouse body mass). Nonspecific adhesion of MBControl at the same injection dose was negligible. In addition, the targeted contrast ultrasound signal of MBVEGFR2 decreased with lower microbubble doses, whereas nonspecific adhesion of MBControl increased with higher microbubble doses. The dose of 5 × 10 microbubbles per animal is now the lowest injection dose on record for ultrasound molecular imaging to achieve statistically significant detection of molecular targets in vivo. Findings in this study provide us with further guidance for future developments of clinically translatable ultrasound molecular imaging applications using a lower dose of microbubbles.

Development of Radiolabeled Molecular Imaging Probes for in Vivo Analysis of Biological Function

Molecular imaging is a newly emerging field aimed at advancing our understanding of biology and medicine through the noninvasive in vivo investigation of cellular molecular events involved in normal and pathologic processes. In this field, researchers and/or clinicians are combining modern tools of molecular and cell biology with state of the art technology in order to noninvasively image living subjects. Various imaging modalities such as optics (fluorescence and luminescence), nuclear magnetic resonance imaging, ultrasound, and radiation are being used to visually capture and study molecular and cellular events in living organisms. Among these modalities, nuclear medical molecular imaging uses radionuclides [i.e., positron emission tomography (PET) and single-photon emission computed tomography (SPECT)], and has characteristic properties that allow researchers and/or clinicians to obtain functional images of living subjects with high sensitivity. Translational molecular imaging, a research step between animal experiments and the clinical setting, has been successful when using nuclear medical molecular imaging. This approach leads to better methods for studying biological processes, as well as for diagnosing and managing diseases. In this review, two topics associated with our research on nuclear medical molecular imaging are summarized: (1) the development of a nuclear medical molecular imaging probe that targets cerebral nicotinic acetylcholine receptors (nAChRs), and the translational molecular imaging research conducted using this nAChR imaging probe; and (2) the development of oxygen-dependent degradable nuclear medical molecular imaging probes that target hypoxia-inducible factor-1-active tumor microenvironments.

Recent Advances in Targeting Tumor Energy Metabolism with Tumor Acidosis as a Biomarker of Drug Efficacy.

Cancer cells employ a deregulated cellular metabolism to leverage survival and growth advantages. The unique tumor energy metabolism presents itself as a promising target for chemotherapy. A pool of tumor energy metabolism targeting agents has been developed after several decades of efforts. This review will cover glucose and fatty acid metabolism, PI3K/AKT/mTOR, HIF-1 and glutamine pathways in tumor energy metabolism, and how they are being exploited for treatments and therapies by promising pre-clinical or clinical drugs being developed or investigated. Additionally, acidification of the tumor extracellular microenvironment is hypothesized to be the result of active tumor metabolism. This implies that tumor extracellular pH (pHe) can be a biomarker for assessing the efficacy of therapies that target tumor metabolism. Several translational molecular imaging methods (PET, MRI) for interrogating tumor acidification and its suppression are discussed as well.

Highlights lecture EANM 2014: "Gimme gimme gimme those nuclear Super Troupers".

The EANM Congress 2014 took place in Gothenburg, Sweden, from 18 to 22 October under the presidency of Prof. Wim Oyen, chair of the EANM Scientific Committee. Prof. Peter Gjertsson chaired the Local Organizing Committee, according to the standardized EANM congress structure. The meeting was a highlight for the multidisciplinary community that forms the heart and soul of nuclear medicine; attendance was exceptionally high. In total almost 5,300 participants came to Gothenburg, and 1,397 colleagues participated via the EANM LIVE sessions (http://eanmlive.eanm.org/index.php). Participants from all continents were presented with an excellent programme consisting of symposia, scientific and featured sessions, CME sessions, and plenary lectures. These lectures were devoted to nuclear medicine therapy, hybrid imaging and molecular life sciences. Two tracks were included in the main programme, clustering multi-committee involvement: the 5th International Symposium on Targeted Radionuclide-therapy and Dosimetry (ISTARD) and the first Molecules to Man (M2M) track, an initiative of the EANM Committees for Translational Molecular Imaging, Radiopharmacy and Drug Development. The industry made a substantial contribution to the success of the congress demonstrating the latest technology and innovations in the field. During the closing Highlights Lecture, a selection of the best-rated abstracts was presented including diverse areas of nuclear medicine: physics and instrumentation, radiopharmacy, preclinical imaging, oncology (with a focus on the clinical application of newly developed tracers) and radionuclide therapy, cardiology and neurosciences. This Highlights Lecture could only be a brief summary of the large amount of data presented and discussed during the meeting, which can be found in much greater detail in the congress proceedings book, published as Volume 41, Supplement 2 of the European Journal of Nuclear Medicine and Molecular Imaging in October 2014.

Integrin-Targeted Molecular Imaging of Experimental Abdominal Aortic Aneurysms by 18 F-labeled Arg-Gly-Asp Positron-Emission Tomography

Both inflammation and neoangiogenesis contribute to abdominal aortic aneurysm (AAA) disease. Arg-Gly-Asp-based molecular imaging has been shown to detect the integrin αvβ3. We studied a clinical dimeric (18)F-labeled Arg-Gly-Asp positron-emission tomography (PET) agent ((18)F-FPPRGD2) for molecular imaging of experimental AAAs. Murine AAAs were induced in Apo-E-deficient mice by angiotensin II infusion, with monitoring of aortic diameter on ultrasound. AAA (n=10) and saline-infused control mice (n=7) were injected intravenously with (18)F-FPPRGD2, as well as an intravascular computed tomography contrast agent, then scanned using a small-animal PET/computed tomography scanner. Aortic uptake of (18)F-FPPRGD2 was quantified by percentage-injected dose per gram and target-to- =0.003; median target-to- =0.0008). Ex vivo autoradiography demonstrated high uptake of (18)F-FPPRGD2 into the AAA wall, with immunohistochemistry showing substantial cluster of differentiation (CD)-11b(+) macrophages and CD-31(+) neovessels. Target-to- =-0.29, P=0.41) but did strongly correlate with both mural macrophage density (r=0.79, P=0.007) and neovessel counts (r=0.87, P=0.001) on immunohistochemistry. PET imaging of experimental AAAs using (18)F-FPPRGD2 detects biologically active disease, correlating to the degree of vascular inflammation and neoangiogenesis. This may provide a clinically translatable molecular imaging approach to characterize AAA biology to predict risk beyond size alone.