Current Medical Imaging - Volume 6, Issue 1, 2010

Molecular imaging techniques play roles in the development of novel therapies since they generate information on target expressions, pathway activities and cell functions in the intact organism. The imaging technologies enable the comprehensive characterization of therapeutic intervention. The 5th Hangzhou International Molecular Imaging Conference (HIMIC) annual meeting in Advances in Molecular Imaging From Bench to Bedside was held October 22 - 24, 2009, in Hangzhou, Zhejiang, China. HIMIC is the first international conference on molecular imaging held in China sponsored by Zhejiang University and the Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, China. Zhejiang University is the top-3 and largest national university in China, and the Second Affiliated Hospital of Zhejiang University is the leading institute in molecular imaging in China. This annual conference was initiated in 2005. This special conference is focused on advances in molecular imaging. There were 150 attendees including 12 invited speakers. Young Investigator awards were judged by committee members (invited speakers) and presented by Committee Chairman, Prof. Michael Welch (University of Washington, St. Louis, MO). Topics covered were advances in bioimaging applications in pre-clinical drug discovery, drug development and regulatory developments in oncology, effect of contrast agent in PET/CT, dosimetric determination for a radiotheranostic agent, imaging technology in drug development, and validation of imaging agents on new molecular targets. The meeting was concluded by Prof. Hong Zhang (Second Affiliated Hospital of Zhejiang University, China), and Prof. E. Edmund Kim, MD (University of Texas MD Anderson, Houston, TX) discussed prediction and evaluation of therapeutic response by utilizing molecular imaging. In this conference, the values of new radiopharmaceuticals for PET in pre-clinic studies and patients were overviewed by Prof. Michael Welch. He addressed that new radiopharmaceuticals provide measurements of the biochemistry and biology of disease for more direct assessments of the impact of a drug on disease to stratify patients into treatment responders and nonresponders. He pointed out that the challenges were the availability of isotopes, methods for automation, regulatory compliance, and intellectual rights. Molecular theranostic approaches of cancers using kit probes were overviewed by Prof. David Yang (UT MD Anderson, Houston, TX). He reported the use of chelators to trap metallic isotopes for theranostic applications. The values of PET/CT and SPECT/CT in clinic applications were reviewed by Prof. Zachary Grossman, MD (Roswell Park Cancer Institute, Buffalo, New York) and Prof. E. Edmund Kim, MD. Both emphasized that hybrid imaging modalities improve the accuracy of clinical trials. However, imaging standardization and harmonization of the centralized IND are important in imaging. Molecular imaging in cardiology and neurology were reported by Prof. Carrio Ignasi, MD (Autonomous University of Barcelona, Spain) (presented by Assistant Prof. Mei Tian, MD at University of Texas MD Anderson, Houston, TX). They reported the approaches using reporter gene imaging and cell trafficking for nuclear cardiology and novel tracers for neurology. Prof. June-Key Chung, MD (Seoul National University, Korea) also reported the use of radioiodine as a sodium iodide symporter to assess NIS gene expression in thyroid cancer. These speakers emphasize that molecular imaging provide pharmacokinetics in disease tissue and throughout the other tissues of body linked to the pharmacokinetics in blood and use drugs or drug analogs as imaging probes to assess target occupancy for determining dosing and whether the drug is efficacious. Prof. Yasuhisa Fujibayashi (University of Fukui, Japan) reported the use of Cu-ATSM in PET imaging and radionuclide therapy in cancer stem cells. He addressed the value of using a hypoxic marker to assess cancer stem cell-rich region. Reduce respiratory motion artifact techniques during imaging were reviewed by Associ Prof. Osama Mawlawi (University of Texas MD Anderson, Houston, TX). He also discussed the use of low dose CT to PET scanners for treatment planning. Assis Prof. Keon Wook Kang, MD (Seoul National University, Korea) reported that Ga-68 NOTA-RGD, an angiogenesis tracer, allows quicker assessment of drug responses to colorectal patients into different drug regimens, either switching refractory patients to another drug or drug combination (responder vs non-responder). Efficient synthesis of F-18 labeled peptide with high binding affinity was overviewed by Dr. Ananth Srinivasan (Bayer Schering Pharma, Germany). The prospective for molecular imaging should be focused on emerging trends (horizon technologies, government/field initiatives) in molecular imaging and emphasized on accelerating drug development with fast approval process of candidate drugs using molecular imaging technologies. The website for this meeting can be found at http://www.molecularimaging.ac.cn

Radioactive iodine therapy has played an important role in the management of differentiated thyroid cancer (DTC) since specific accumulation of iodide in the thyroid gland was initially reported. The incidence of thyroid cancer is increasing in many countries including Korea. Conventional RIT has an effect on the treatment of metastatic thyroid cancer. To obtain the effects of I-131 therapy, tumors must accumulate iodide. However, about 20-30% of thyroid cancers do not accumulate iodide; they have a poor prognosis compared to DTC. For such cases, there are several methods available to increase the effects of RIT. One is by increasing the administration dose to the maximal safe dose to increase the delivery of I-131 to the tumor. Another is using retinoic acid to induce re-differentiation of cancer cells and to restore the accumulation of iodide. By such efforts, the clinical outcome of thyroid cancer can be improved. Historically, radioiodine therapy was started at the Seoul National University Hospital in 1960 when the “Radioisotope Clinic” was opened; this service has played a central role in nuclear medicine practice in Korea. In this paper, we summarized the data and experience with I-131 treatment on recurrent/metastasis of DTC at the Seoul National University Hospital.

Hypoxia, a condition of insufficient O2 to support metabolism, occurs when tumor outgrows its vascular supply. As the tumor cells gradually become hypoxic, they adapt by up-regulating the production of numerous proteins that promote their survival and metastatic spread. These changes result in patients with hypoxic tumors invariably experience poor outcome to treatment. Accordingly, the development of assays for the detection of hypoxia in patients in order to predict outcome and identify patients with a worse prognosis and/or patients that would benefit from appropriate treatments is of potential interest to researchers and clinicians. A variety of invasive and noninvasive approaches have been developed to detect tumor oxygenation. These approaches including oxygen-sensitive electrodes and hypoxia marker techniques using various labels that can be detected by different methods such as autoradiography, immunohistochemistry, nuclear medicine imaging and magnetic resonance imaging. In this review, we will discuss the non-invasive, potentially providing a quantitative and high resolution three-dimensional molecular imaging modality with positron emission tomography which is available to measure tumor hypoxia.

The precise neurobiological processes underlying epilepsy and epileptogenesis remain unknown. Animal models have been widely used to investigate the neurobiology, consequences and treatment of epileptic seizures and epilepsy. Small animal Positron Emission Tomography (microPET) can permit assessment of brain metabolic activity in the living animal, which cannot be accomplished by the traditional neuroscience techniques (e.g., histology, immunohistochemistry and autoradiography). It allows investigation of the neurobiological changes during epileptogenesis in the animal models and the variability caused by inter-animal differences can be removed since the same animal is used repeatedly. Moreover, microPET can also be used to investigate the biological effects of novel treatment strategies.

As FDG-PET and FDG-PET/CT have gained acceptance, a number of beliefs regarding these techniques have become ingrained in clinicians; the time has come to challenge some of these beliefs, to better serve our patients and perhaps create room for novel ideas that may enhance metabolic imaging. Common beliefs that bear re-examination include: (1) The best radionuclide method to detect bone metastases is a conventional Tc-99m-MDP bone scan, because this scan visualizes the metabolism of bone, and bone metastases, by definition, go to bone, where they disrupt normal bone metabolism. (2) PET imaging is sensitive but far inferior to CT in terms of spatial resolution. PET can never expect to define tiny malignant lesions, 2-4 mm in diameter, surrounded by centimeters of soft tissue. (3) FDG-PET is superior to other imaging techniques for the detection of many solid tumors, but some tumors do not markedly accumulate FDG, and probably little can be done about that. Analysis indicates that none of these common beliefs are true.

Drug response is a fundamental concept that describes the phenomenon in essence whereby some patients benefit from a particular therapy whereas others, despite apparently identical clinical and histopathologic characteristics. Monitoring therapeutic response has been a crucial part of clinical oncology with two approaches. One is to measure markers specifically secreted by tumor cells into the blood, and the other approach uses changes in tumor size. However, their limitations have been well recognized. Intense efforts have been made to understand the mechanisms underlying the therapeutic responsiveness or at least to identify parameters that correlate closely with the response. However, these molecular predictors such as genes are far from perfect as known in breast cancers with HER2 and trastuzumab. Drug actions are related to receptor or enzyme activity, and the current assays are purely morphologic studies. However, imaging with radiolabeled drugs reflects not only the presence or absence but also functioning status of specific receptor or enzyme. Radiolabeled drugs may predict or detect favorable vs unfavorable patients to specific therapy. We have radiolabeled various drugs and agents such as taxol, folate, guanine, metronidazole, annexin, glucosamine, endostatin, antiphosphotyrosine antibody and estradiol, and radiolabled estradiol is specific to predict and monitor hormonal therapy.

The Huisgen 1,3-dipolar cycloaddition of azides and alkynes, one of the most powerful click reactions which result in 1,2,3-triazoles has been widely used in various research areas. Recent years have seen rapid development of click labeling fluorine-18 peptides and some of these novel imaging probes have been evaluated for Positron emission tomography (PET). This mini review is aiming to provide a brief overview on the development of the click labeling fluorine-18 peptides for PET.

Magnetic resonance imaging (MRI) is a non-invasive and high resolution imaging technique and becomes a powerful diagnostic tool in the clinic. With the applications of MRI becoming more and more dependent on contrast agents, it is particularly important to develop efficient contrast agents. This article describes how to design an efficient dendritic Gd-DTPA complex for MRI contrast agents.

Purpose: Positron emission tomography (PET) and single photon emission computed tomography (SPECT) tracers have been applied to pharmacokinetic, pharmacodynamic, dose-finding, and proof-of-concept studies. PET/SPECT tracers could non-invasively assess treatment endpoints for diseases which used to rely on biopsies and histopathological assays. 18F-Fluorodeoxyglucose (FDG) is a gold standard for PET to detect unsuspected distant metastases in cancers. However, 18F-FDG has difficulties in distinguishing between inflammation/infection related masses versus cancer recurrence. Also, tumors with low glycolysis show poor FDG uptake, which leads to the high rate of false-negative results. Recent studies indicate that radiolabeled tyrosine derivatives using L-type amino acid transporters (LAT) can differentiate cancer from inflammation. Methods: We have synthesized 99mTc- and 68Ga-labeled chelator-based tyrosine analogs and their potential uses as kit probes for molecular radiotheranostic of tumors were evaluated. Results: The active ingredient in the kit is considered a drug substance, which allows standardization for chemistry, manufacturing and control (CMC). CMC is a crucial element in the centralized Investigational New Drugs (IND) process, and can be readily solved with kit probes. Conclusion: The use of PET and SPECT tracers has also helped to control and monitor dosage for increased safety and effectiveness, which have high impact on economy.

Molecular imaging is the visualization, characterization, and measurement of biological processes at the molecular and cellular levels in humans and other living systems. In the past decade, there has been sufficient experience with specifically targeted therapeutic or diagnostic imaging agents that we must begin moving them from bench to bedside. However, crucial prerequisites for the development of safe pre-clinical protocols in molecular imaging research are needed through suitable large animal models since most of previous experiments were carried out on rodents. This review is focus on the translational molecular imaging research on drug development and radiopharmaceutical drug development, animal model selection, experimental design, the obstacle and future challenges of translational molecular imaging.

In cancer treatment, molecular targeting therapy has rapidly progressed. With the improvement of molecular targeting therapy, the need for evaluating bio-marker is increasing. To decide appropriate target agent, evaluating the status of target molecule is mandatory. Anti-angiogenic therapy is widely used as a clinical strategy for cancer treatment such as colorectal cancer, lung cancer. In case of anti-angiogenic treatment, angiogenesis imaging could select the patients who respond to anti-angiogenic treatment. There are several methods to evaluate angiogenesis. Angiogenesis could be evaluated by vascular structure, hemodynamic changes. However, none of those parameters are present in the angiogenic activity of tumor. Furthermore, the results of vascular structure or hemodynamic changes could not predict the response. RGD peptide is a ligand of integrin αvβ3 which over-expresses on the endothelium of neo-vascularization. Using radiolabeled RGD PET, we could evaluate the angiogenic activity of tumor, and it could be related with the response to antiangiogenic drugs. In this paper, we summarized the factors predicting the response. In this paper, we also introduced our preliminary experience of 68Ga-RGD PET in patients with colorectal cancer.