Molecular imaging: challenges of bringing imaging of intracellular targets into common clinical use

Molecular imaging (MI) takes advantage of several new techniques to detect biomarkers or biochemical and cellular processes, with the goal of obtaining high sensitivity, specificity and signal‐to‐noise ratio imaging of disease. The imaging modalities bearing the most promise for MI are positron emission tomography (PET), single photon emission computer tomography (SPECT) and different optical imaging techniques with high sensitivity. Also magnetic resonance imaging (MRI) with contrast agents like ultra‐small superparamagnetic iron oxide particles (USPIO), magnetic resonance spectroscopy and ultrasound imaging with contrast agents may be useful approaches. MI techniques have been used in the clinic for many years, i.e. PET imaging using ¹⁸ F‐labeled fluorodeoxyglucose. Animal studies have during the last years revealed great potential for MI also with several other agents. The focus of the present article is the challenges of clinical imaging of intracellular targets following intravenous injection of the agents. Thus, the great challenge of getting enough contrast agent into the cytosol and at the same time obtaining a low signal from tissue just outside the diseased area is discussed. Copyright © 2012 John Wiley & Sons, Ltd.     

State of the Art in Cardiac Hybrid Technology: PET/MR

Simultaneous PET/MRI is an emerging technique combining two powerful imaging modalities in a single device. The wide variety of available tracers for perfusion and metabolic studies and the high sensitivity of positron emission tomography (PET) combined with the high spatial resolution and soft tissue contrast of magnetic resonance imaging (MRI) in depicting cardiac morphology and function as well as MRI’s absence of ionizing radiation makes PET/MRI very attractive to radiologists and clinicians. Nevertheless, PET/MR scientific and clinical promise is to be considered in the context of numerous technical challenges that hinder its use in the clinical setting. For example, in order for a PET system to work correctly within an MR field, major changes are required to the photon detection chain such as the elimination of photomultiplier tubes, etc. Another significant limitation of PET/MRI is the lack of an electron density map (as is the case with PET-CT) that can be readily obtained from MRI (the latter measures proton not electron density) and used to correct PET data for attenuation. Moreover, as with PET-CT, cardiac and respiratory motions cause image degradations that affect image quality and accuracy both in static and dynamic PET imaging. As a result, overcoming these (and other) technical limitations is a very active area of research both in academic institutions as well as industry. In this paper, we review recent literature on cardiac PET/MRI, present the state-of-the-art of this technology, and explore promising preclinical and clinical cardiac applications where PET/MRI could play a substantial role.     

Imaging of the lymphatic system: new horizons

The lymphatic system is a complex network of lymph vessels, lymphatic organs and lymph nodes. Traditionally, imaging of the lymphatic system has been based on conventional imaging methods like computed tomography (CT) and magnetic resonance imaging (MRI), whereby enlargement of lymph nodes is considered the primary diagnostic criterion for disease. This is particularly true in oncology, where nodal enlargement can be indicative of nodal metastases or lymphoma. CT and MRI on their own are, however, anatomical imaging methods. Newer imaging methods such as positron emission tomography (PET), dynamic contrast‐enhanced MRI (DCE‐MRI) and color Doppler ultrasound (CDUS) provide a functional assessment of node status. None of these techniques is capable of detecting flow within the lymphatics and, thus, several intra‐lymphatic imaging methods have been developed. Direct lymphangiography is an all‐but‐extinct method of visualizing the lymphatic drainage from an extremity using oil‐based iodine contrast agents. More recently, interstitially injected intra‐lymphatic imaging, such as lymphoscintigraphy, has been used for lymphedema assessment and sentinel node detection. Nevertheless, radionuclide‐based imaging has the disadvantage of poor resolution. This has lead to the development of novel systemic and interstitial imaging techniques which are minimally invasive and have the potential to provide both structural and functional information; this is a particular advantage for cancer imaging, where anatomical depiction alone often provides insufficient information. At present the respective role each modality plays remains to be determined. Indeed, multi‐modal imaging may be more appropriate for certain lymphatic disorders. The field of lymphatic imaging is ever evolving, and technological advances, combined with the development of new contrast agents, continue to improve diagnostic accuracy. Published in 2006 by John Wiley & Sons, Ltd.     

Design of ProCAs (Protein‐Based Gd3+ MRI Contrast Agents) with High Dose Efficiency and Capability for Molecular Imaging of Cancer Biomarkers

Magnetic resonance imaging (MRI) is the leading imaging technique for disease diagnostics, providing high resolution, three‐dimensional images noninvasively. MRI contrast agents are designed to improve the contrast and sensitivity of MRI. However, current clinically used MRI contrast agents have relaxivities far below the theoretical upper limit, which largely prevent advancing molecular imaging of biomarkers with desired sensitivity and specificity. This review describes current progress in the development of a new class of protein‐based MRI contrast agents (ProCAs) with high relaxivity using protein design to optimize the parameters that govern relaxivity. Further, engineering with targeting moiety allows these contrast agents to be applicable for molecular imaging of prostate cancer biomarkers by MRI. The developed protein‐based contrast agents also exhibit additional in vitro and in vivo advantages for molecular imaging of disease biomarkers, such as high metal‐binding stability and selectivity, reduced toxicity, proper blood circulation time, and higher permeability in tumor tissue in addition to improved relaxivities.     

Liver metastases from colorectal cancer: imaging with superparamagnetic iron oxide (SPIO)-enhanced MR imaging,computed tomography and positron emission tomography

The literature about superparamagnetic iron oxide-enhanced MR imaging, computed tomography (CT) and PET (positron emission tomography using fluorine-18 labelled fluoro-deoxy-glucose) in detection of liver metastases (LM) from colorectal cancer is reviewed in this update. Special emphasis is given to studies with surgical standard of reference allowing for the lesion-by-lesion sensitivity to be determined. Based on the review, it is concluded that state-of-the-art anatomical imaging, e.g., SPIO-enhanced MR imaging and multidetector CT (MDCT), must be considered more sensitive than PET in detection of individual LM, due to technical developments in MR imaging, such as liver specific contrast agents, modern sequences and high performance gradients, and in modern MDCT have increased the performance of these modalities. MR imaging with a liver specific contrast agent is recommended for the preoperative evaluation before liver surgery for LM because of high sensitivity and better discrimination between small LM and cysts compared to MDCT. PET or PET/CT can be used for detection of extra-hepatic tumor before liver surgery.     

Cardiac PET/MRI

Medical imaging plays an important role in clinical management of patients with cardiac diseases and in preclinical and clinical research. The recent availability of hybrid PET/MRI devices that combine positron emission tomography (PET) with magnetic resonance imaging (MRI) opens up new opportunities. Technical advancements have been necessary to make the two systems with different underlying principles work well together. Growing evidence points to a significant value of this novel modality for imaging of the myocardium and the coronary arteries in order to gain broad insight into the morphological, functional, molecular and cellular aspects of cardiac pathophysiology. PET/MRI can deliver the combined information of stand-alone PET and MRI with improved spatial and temporal co-registration; it can additionally be used to improve PET image quality and quantification accuracy by addressing factors such as motion and partial volume effects, making PET/MRI more than its parts.     

Advances in Molecular Imaging: Plaque Imaging

Recent advances in nuclear plaque imaging aim to achieve noninvasive identification of vulnerable atherosclerotic plaques using positron emission tomography (PET) with ¹⁸F-fluorodexoyglucose (FDG) and novel tracers targeting molecular markers of inflammation and other active metabolic processes. Nuclear imaging of atherosclerosis has been demonstrated in multiple vascular beds, including the carotid, aorta, peripheral and coronary arteries—but significant challenges remain, especially for coronary imaging. The advantage of PET over other molecular imaging modalities is its superior sensitivity, however, low spatial resolution means that images must be co-registered with computed tomography (CT) or magnetic resonance imaging (MRI) for precise anatomical localization of the PET signal. Such hybrid techniques provide the best hope for early detection of prospective culprit lesions—which may, in the coronary vasculature, appear falsely low-risk using conventional coronary angiography or stress imaging. Current hot topics in nuclear plaque imaging include the use of FDG-PET for therapeutic monitoring in drug development, identification of imaging biomarkers to evaluate cardiovascular risk, and the development of novel tracers against an array of biologically important markers of atherosclerosis. The purpose of this article is to review these recent advances in nuclear plaque imaging.     

全身MR/PET联合成像:技术构想、临床工作流程及初步结果

长期以来,科研人员、放射科专家及核医学专家都在致力于MR/PET联合成像技术的研究.这一联合技术结合了MR成像所特有的性质(如极好软组织对比度、高空间和时间分辨率及组织功能成像)和PET成像所具有高灵敏度特性,因而在临床疾病诊断方面具有重大应用前景.西门子近期推出的BiographmMR系统率先在3T MR成像仪上完全...     

SimPET: a Preclinical PET Insert for Simultaneous PET/MR Imaging

Purpose

SimPET/M7 system is a small-animal dedicated simultaneous positron emission tomography and magnetic resonance imaging (PET/MRI) scanner. The SimPET insert has been upgraded from its prototype with a focus on count rate performance and sensitivity. The M7 scanner is a 1-T permanent magnet-based compact MRI system without any cryogens. Here, we present performance evaluation results of SimPET along with the results of mutual interference evaluation and simultaneously acquired PET/MR imaging.

Procedures

Following NEMA NU 4-2008 standard, we evaluated the performance of the SimPET system. The M7 MRI compatibility of SimPET was also assessed by analyzing MRI images of a uniform phantom under different PET conditions and PET count rates with different MRI pulse sequences. Mouse imaging was performed including a whole-body ¹⁸F-NaF PET scan and a simultaneous PET/MRI scan with ⁶⁴Cu-NOTA-ironoxide.

Results

The spatial resolution at center based on 3D OSEM without and with warm background was 0.7 mm and 1.45 mm, respectively. Peak sensitivity was 4.21 % (energy window?=?250–750 keV). The peak noise equivalent count rate with the same energy window was 151 kcps at 38.4 MBq. The uniformity was 4.42 %, and the spillover ratios in water- and air-filled chambers were 14.6 % and 12.7 %, respectively. In the hot rod phantom image, 0.75-mm-diameter rods were distinguishable. There were no remarkable differences in the SNR and uniformity of MRI images and PET count rates with different PET conditions and MRI pulse sequences. In the whole-body ¹⁸F-NaF PET images, fine skeletal structures were well resolved. In the simultaneous PET/MRI study with ⁶⁴Cu-NOTA-ironoxide, both PET and MRI signals changed before and after injection of the dual-modal imaging probe, which was evident with the exact spatiotemporal correlation.

Conclusions

We demonstrated that the SimPET scanner has a high count rate performance and excellent spatial resolution. The combined SimPET/M7 enabled simultaneous PET/MR imaging studies with no remarkable mutual interference between the two imaging modalities.

     

Cardiac imaging

Congestive heart failure is a state of inadequate cardiac function under various etiologies. Cardiac imaging plays an important role for accurate detection of heart failure, assessment of severity of LV function, and precise analysis of tissue function in vivo. Recently, multislice CT(MSCT), magnetic resonance imaging (MRI), and positron emission tomography(PET) have been rapidly developed for clinical use for assessing patients with congestive heart failure. MSCT has been used for accurate assessment of LV function. Due to high spatial resolution, MSCT permits assessment of coronary stenosis without cardiac catheterization. MRI permits assessment of LV function and also tissue function. Particularly, infarcted myocardium is accurately delineated as an area of delayed enhancement by contrast enhancement MRI study. PET has been used for accurate assessment of myocardial viability based on the persistence of myocardial glucose metabolism. In addition, a various new PET tracers permit molecular and cellular function, such as neurotransmission and receptor function in vivo. These new imaging technique has a potential role for assessing risk stratification and providing appropriate treatment strategy.     

Application of MR/PET in Oncologic Imaging

The present review aims to depict the possibilities offered by hybrid imaging with magnetic resonance positron emission tomography (MR/PET). Recently, new whole-body MR/PET scanners were introduced allowing for the combination of both modalities outside the brain. This is a challenge for both modalities: For MRI, it is essential to provide anatomical images with high resolution. Additionally, diffusion-weighted imaging (DWI), proton spectroscopy, but also dynamic contrast-enhanced imaging plays an important role. With regard to PET, the technical challenge mainly consists of obtaining an appropriate MR-based attenuation correction for the PET data. Using MR/PET, it is possible to acquire morphological and functional data in one examination. In particular, children and young adults will benefit from this new hybrid technique, especially in oncologic imaging with multiple follow-up examinations. However, it is expected that PET/CT will not be replaced completely by MR/PET because PET/CT is less cost-intensive and more widely available. Moreover, in lung imaging, MRI limitations still have to be accepted. Concerning research, simultaneous MR/PET offers a variety of new possibilities, for example cardiac imaging, functional brain studies or the evaluation of new tracers in correlation with specific MR techniques.     

Cardiovascular PET/MRI: Technical Considerations and Outlook

Purpose of Review

We aim to provide insights into current and future applications of cardiac PET/MRI and the logistical issues one should consider when implementing a program using this still novel technology.

Recent Findings

Since their introduction around 15 years ago, PET/CT and SPECT/CT hybrid imaging devices saw high clinical utilization, which was driven clearly by oncology. Fortunately, the basic availability in a clinical setting enabled the investigation of the cardiac imaging perspective and facilitated numerous research activities. Given the fact that cardiac MRI is a very attractive research field with an increasing clinical utilization, PET/MRI raised the expectation of innovative imaging scenarios with synergistic applications. Integrating molecular imaging with a multitude of PET agents and the high temporal and spatial resolution of MRI are ideally suited for novel applications having especially a reduced burden of ionizing radiation and potentially a lack of contrast media in mind.

Summary

The technical complexity and consequentially the considerable amount of monetary investment resulted until today in a limited availability and experience. However, the potential of these systems are currently unsurpassed as they really implement a “best of both worlds” approach.

     

MR molecular imaging of HER‐2 in a murine tumor xenograft by SPIO labeling of anti‐HER‐2 affibody

In vivo molecular imaging is a rapidly growing research area both for basic and clinical science. Non‐invasive imaging of in vivo conditions at the molecular level increases understanding of the biological characteristics of normal and diseased tissues without the need for invasive surgical procedures. Among the various imaging modalities, magnetic resonance imaging (MRI) has garnered interest as a molecular imaging modality due to its high spatial resolution. Here, we have demonstrated that the combined use of HER‐2 targeting affibody, a small 7 kDa molecule that behaves similarly to antibodies, and superparamagnetic iron oxide (SPIO) can non‐invasively image HER‐2 expressing cells or tissues both in vitro and in vivo by MRI. This preliminary study demonstrates that affibody‐SPIO is a feasible, target‐specific contrast agent for in vivo MR molecular imaging. Copyright © 2010 John Wiley & Sons, Ltd.     

Optimization of ex vivo CT- and MR- Imaging of Atherosclerotic Vessel Wall Changes

OBJECTIVE: To optimize a methodology for ex vivo imaging of atherosclerotic vessel wall changes using multidetector-row computed tomography (MDCT) and multi-contrast magnetic resonance imaging (MRI). METHODS: In phantom studies and studies on intact ex vivo porcine and human hearts, various filling mixtures of MDCT and MRI contrast agents have been evaluated, to enable filling and distension of the coronary arteries for optimal visualization of atherosclerotic vessel wall changes with both techniques. Various proportions of methyl cellulose, iodine-containing CT contrast agent and paramagnetic MR contrast agent containing iron-oxide particles have been tested. Imaging parameters have been optimized for high resolution plaque imaging using a four detector-row CT scanner and a 1.5 T MR system. RESULTS: Phantom studies and studies on ex vivo porcine and human hearts demonstrated optimal proportion of methyl cellulose and CT contrast agent to be 98% vs. 2%, and 75% vs. 25% of methyl cellulose vs. MR contrast agent, respectively. These proportions provided optimal opacification of the vessel lumen in the MDCT images with 250 Hounsfield Units, and good signal suppression within the vessel lumen in the MR images, resembling in vivo imaging techniques. After retrospective matching with histopathology, atherosclerotic lesions of the human ex vivo specimens could be identified on MRI and MDCT images. CONCLUSION: Using an optimized mixture of methyl cellulose, MDCT and MRI contrast agents, visualization of atherosclerotic vessel wall changes is feasible, and applicable to various ex vivo models.     

Combined imaging with multi-detector row computed tomography and diffusion-weighted imaging in the detection of pancreatic cancer

Pancreatic cancer is one of the most aggressive malignant tumor types. Its prognosis is extremely poor without early detection, and an accurate diagnosis with imaging techniques is vital for any chance of long-term survival after treatment. Despite the great technical advances that have been made with various kinds of imaging equipment, detection of pancreatic cancer is unsatisfactory, and new modalities are required. Diffusion-weighted imaging (DWI) on magnetic resonance imaging (MRI) has high sensitivity and specificity for the detection of pancreatic cancer; however, it does not provide anatomic information. Quite often, the necessary spatial correlation of a high-intensity area with anatomic structures is constrained. If it becomes possible to combine the imaging technique of DWI with multi-detector row computed tomography (MDCT), such as is done with positron emission tomography (PET) and computed tomography (CT), it is expected that the early diagnostic capability will improve. The objective of this study was to introduce combined imaging with DWI and CT into clinical practice to improve the diagnosis of pancreatic cancer. In the current report, we demonstrate a clinical attempt to combine DWI on MRI with the anatomical accuracy of MDCT for two patients of pancreatic adenocarcinoma. Analysis of these two patients revealed that the combined images corresponded precisely to the operative findings. Thus, the combined imaging with DWI and MDCT is useful for the detection of the pancreatic cancer.     

State of the Art Hybrid Technology: PET/CT

In the recent years, hybrid positron emission tomography (PET)/computed tomography (CT) scanners have been increasingly utilized in cardiac applications. PET imaging quality has been improved by the use of new scintillators, small detector element size, and fully 3D iterative reconstruction techniques with time-of-flight information and resolution recovery. Further quality enhancements for cardiac imaging can be obtained by tracking and correcting for cardiac and breathing motion with respiratory gating devices and advanced software techniques. The primary tracers used for PET/CT cardiac imaging are Rubidium-82 (⁸²Rb) and Nitrogen-13-ammonia (¹³N-ammonia) and 18-F fluorodeoxyglucose used for myocardial viability imaging. A new F-18 perfusion tracer (F-18 Flurpiridaz) is being evaluated. High-resolution multi-slice CT component of the hybrid scanner allows accurate attenuation correction for PET, measurement of CT calcium, and contrast CT angiography. Hybrid PET/CT protocols have demonstrated increased diagnostic accuracy for the detection of obstructive disease compared with standalone techniques. Radiation dose to the patient is a concern in hybrid imaging because multiple scans are performed in one scanning session. 3D PET acquisition combined with the new low-dose CT protocols can reduce the doses significantly. Hybrid PET/CT scanners have also been utilized for anatomically-guided molecular imaging of plaque biology in the carotid vessels, aorta, and coronary vessels. This review summarizes the state-of-the-art hybrid imaging PET/CT instrumentation and advances in the image quality related to cardiac imaging.     

Non-invasive Imaging in Gene Therapy.

Several methods are available for non-invasive imaging of gene delivery and transgene expression, including magnetic resonance imaging (MRI), single photon emission tomography (SPECT)/positron emission tomography (PET), and fluorescence and bioluminescence imaging. However, these imaging modalities differ greatly in terms of their sensitivity, cost, and ability to measure the signal. Whereas MRI can produce a resolution of approximately 50 mum, optical imaging achieves only 3-5 mm but outperforms MRI in terms of the cost of the imaging device. Similarly, SPECT and PET give a resolution of only 1-2 mm but provide for relatively easy quantitation of the signal and need only nanograms of probe, compared with the microgram or milligram levels required for MRI and optical imaging. To develop safer and more efficient gene delivery vectors, it is essential to perform rigorous in vivo experiments, to image particle biodistribution and transduction patterns, and to quantify the transgene expression profile. Differences between modalities have a significant effect on the resultant imaging resolution for gene therapy. This review describes the methodologies in use and highlights recent key approaches using the latest imaging modalities in gene therapy. Future trends in gene therapy imaging are also discussed.     

Design of functionalized gold nanoparticle probes for computed tomography imaging

The development of new molecules able to efficiently act as long‐circulating computed tomography (CT) contrast agents is one of the most crucial topics in the biomedical field. In the last years, the chance to manipulate materials at the nano‐size level gave new boost to this research, with the specific aim to design innovative nanoprobes. Gold nanoparticles (AuNPs) have showed unique X‐rays attenuation properties which, combined with their easy surface functionalization, makes them ideal candidates for the next generation of contrast agents. In this paper, we present a rational and facile approach to synthesize engineered and water‐stable AuNPs, achieving concentrated colloidal solution with high Hounsfield Units (HU). An accurate control of reagents ratio allowed us to design AuNPs with different shapes, from symmetrical to anisotropic morphology, in a convenient ‘one‐pot’ fashion. Their activity as efficient and reliable CT contrast agents has been evaluated and compared. Moreover, glucosamine‐functionalized gold nanoparticles have been developed ([Au] = 31.20 mg/mL; HU = 2453), in order to obtain a CT contrast agent able to combine spatial resolution with metabolic information. Copyright © 2016 John Wiley & Sons, Ltd.     

Whole-body magnetic resonance imaging and positron emission tomography-computed tomography in oncology

The advent of positron emission tomography-computed tomography (PET-CT) and whole-body magnetic resonance imaging (WB-MRI) has introduced tumor imaging with a systemic and functional approach compared with established sequential, multimodal diagnostic algorithms.Whole-body PET with [18F]-fluoro-2-desoxy-glucose is a useful imaging procedure for tumor staging and monitoring that can visualize active tumor tissue by detecting pathological glucose metabolism. The combination of PET with the detailed anatomical information of multislice computed tomography as dual-modality scanners has markedly increased lesion localization and diagnostic accuracy compared with both modalities as standalone applications.Hardware innovations, such as the introduction of multi-receiver channel whole-body MRI scanners at 1.5 and, recently, 3 T, combined with acquisition acceleration techniques, have made high-resolution WB-MRI clinically feasible. Now, a dedicated assessment of individual organs with various soft tissue contrast, spatial resolution, and contrast media dynamics can be combined with whole-body anatomical coverage in a multiplanar imaging approach. More flexible protocols (eg, T1-weighted turbo spin-echo and short inversion recovery imaging, dedicated lung imaging or dynamic contrast-enhanced studies of the abdomen) can be performed within 45 minutes.Whole-body magnetic resonance imaging has recently been proposed for tumor screening of asymptomatic individuals, and potentially life-changing diagnoses, such as formerly unknown malignancy, have been reported. However, larger patient cohort studies will have to show the cost efficiency and the clinical effectiveness of such an approach.For initial tumor staging, PET-CT has proved more accurate for the definition of T-stage and lymph node assessment, mainly because of the missing metabolic information in WB-MRI. However, new applications, such as magnetic resonance whole-body diffusion-weighted imaging or lymphotropic contrast agents, may significantly increase sensitivity in near future. Whole-body magnetic resonance imaging has shown advantages for the detection of distant metastatic disease, especially from tumors frequently spreading to the liver or brain and as a whole-body bone marrow screening application. Within this context, WB-MRI is highly accurate for the detection of skeletal metastases and staging of multiple myeloma. This article summarizes recent developments of CT/PET-CT and WB-MRI and highlights their performance within the scope of systemic oncological imaging.