Current Pharmaceutical Design - Volume 18, Issue 8, 2012

Nuclear medicine is an intrinsically molecular technology because it often needs the use of radiolabelled molecular probes to collect information from a special biological target. In contrast to morphological imaging procedures like computed tomography (CT) and magnetic resonance imaging (MRI), the use of ‘magic’ radiopharmaceuticals for the imaging of the biochemical changes that come with any disease has allowed nuclear medicine technique as a functional imaging. Radiolabeled compounds of biological interest are required for the preparation of novel radiopharmaceuticals, which is one of the pillars on which nuclear medicine rests. Radiopharmaceuticals, along with imaging instrumentations (PET: positron emission tomography; SPECT: single photon emission computed tomography), play an important role in facilitating the progress of nuclear medicine. The topics chosen for the issue mainly focus on recent advance in the development of radiolabeled in vivo probes for diagnosis and therapy, especially dedicated to heart imaging, tumor imaging, infection and inflammation imaging and tumor therapy. The themed issue highlights an overview of significant radiopharmaceuticals for which radioligands have recently been developed. Human serum albumin (HSA) is a soluble monomeric protein representing about 60% of the overall plasma content. It has been regarded as a ligand-binding and transport protein for different exogenous and endogenous compounds, such as drugs, fluorescent molecules and radioisotopes. HSA has been an ideal carrier for targeted molecular imaging and therapy due to its many advantages. Dr. Meng Yang and coworkers [1] from Stanford University outline the detailed aspects of HSA and the recent development of many HSA-based molecular probes for their applications in cancer molecular imaging including PET/SPECT imaging, MRI and optical imaging. They conclude HSA should be a very promising platform for molecular imaging probe development and biomedical applications. Angiogenesis, the process by which new blood vessels are formed, is a necessary element at the basis of both tumor growth and metastases. Angiogenesis of tumors has gained great attention in the research community for many years. Noninvasive detection of angiogenic activities is of great importance in cancer diagnosis as well as evaluation of cancer therapeutic responses. Many angiogenesisrelated molecular targets have been identified and used in tumor vasculature targeting and imaging. Herein, Dr. Xia Lu and Rongfu Wang [2] from Peking University First Hospital summarize the current status on the research of peptide Arg-Gly-Asp (RGD) and Arg-Arg-Leu (RRL) as well as its derivatives applied in tumor angiogenesis imaging and targeted therapy with nuclear medicine modalities (SPECT and PET). Coronary artery disease (CAD) remains a primary health problem worldwide. Myocardial perfusion imaging is a technique in which radionuclide tracers are used to evaluate myocardial blood flow, as well as myocardial scarring or infarction, in order to diagnose and assess the significance of CAD. Dr. Xiao Lin and co-workers [3] from Key Laboratory of Radiopharmaceuticals, Beijing Normal University, summarize the development of various SPECT and PET radiotracers for myocardial perfusion imaging and illustrate their chemical structures and biological profiles in this review. In addition, the present status and future aspects in myocardial perfusion imaging agents are also discussed. Folate receptor ( FR), which is highly expressed on many tumor types and activated macrophages, is a promising target for imaging and therapy of cancer and inflammation. Folic acid is an important target-specific delivery molecule with high binding affinity for FR. Therefore, the development of folic acid-targeted radioconjugates for imaging and therapy of cancer and inflammation has become a hot subject in radiopharmaceutical field. Dr. Cristina Muller [4] from Paul Scherrer Institute (Switzerland) outline a variety of folic acid radioconjugates and their applications for imaging and therapy of cancer and inflammation. The existing problems, design strategy and the trend for the development of the FR-targeting radiopharmaceuticals are also discussed in this review. Tissue hypoxia results from an insufficient supply of oxygen that compromises biological functions. It is a pathophysiological aspect that is characteristic for many advanced solid tumors. As a clinical interest, to measure tumor hypoxia in assessing the aggressiveness of tumor and predicting the outcome of therapy has become more and more important. Tumor hypoxia can be detected by non-invasive and invasive techniques. Clinical study using polarographic oxygen electrodes to be a tool to measure hypoxia was the first to demonstrate the presence of hypoxia in human tumor and its association with poor prognosis. However, its invasive nature prevents frequent and repeated use. Over the years, functional imaging as a noninvasive method has attracted much attention and many radiolabelled PET and SPECT tracers have been developed for measuring tumor hypoxia. Dr. Zejun Li and Taiwei Chu [5] from Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Peking University, summarize most of the hypoxia-directed radiopharmaceuticals that have been developed in the past decade. In addition, they mention the possible retention mechanism and the existing problems in the related research field. Infection is an important problem that needs accurate and prompt diagnosis for early management to avoid serious complications. The great impact of infection on daily clinical practice has promoted research into more and more accurate diagnostic and therapeutic. Nuclear medicine techniques do not rely on morphologic changes but are based on physiochemical processes in tissues thus making it suitable to visualize infectious foci in early phases. Imaging infection and inflammation is one of the most challenging areas in nuclear medicine. Nowadays, there is a great interest in the development of new radiopharmaceuticals for infection imaging. Dr. Guillermina Ferro-Flores from Instituto Nacional de Investigaciones Nucleares, Mexico and coworkers [6] summarize the recent advances and applications of radiolabeled specific agents to visualize infectious foci by targeting viruses, fungi or bacteria. They conclude until now the radiolabeled antimicrobial peptide (99mTc-UBI 29-41) has been the most promising infection imaging agent in clinical studies. Overall, the area of radiopharmaceutical in nuclear medicine is one rich with ongoing research. More and more novel specific radiolabeled probes for diagnosis and therapy are expected to be used for clinical applications in the future. In closing, it has been a great honor to be a guest editor for this special issue within the field of radiopharmaceutical sciences and assemble six major manuscripts from senior investigators in university as well as in research institute. I would like to thank all contributors and reviewers for their kind cooperation to accomplish this themed issue. REFERENCES [1] Yang M, Hoppmann SS, Chen LX, Cheng Z. Human serum albumin conjugated biomolecules for cancer molecular imaging. Curr Pharm Des 2012; 18(8): 1023-31. [2] Lu X, Wang RF. A concise review of current radiopharmaceuticals in tumor angiogenesis imaging. Curr Pharm Des 2012; 18(8): 1032-40. [3] Lin X, Zhang JB, Wang XB, Tang ZG, Zhang XZ, Lu J. Development of radiolabeled compounds for myocardial perfusion imaging. Curr Pharm Des 2012; 18(8): 1041-57. [4] Müller C. Folate Based Radiopharmaceuticals for imaging and therapy of cancer and inflammation. Curr Pharm Des 2012; 18(8): 1058-83. [5] Li ZJ, Chu TW. Recent advances on radionuclide labeled hypoxia-imaging agents. Curr Pharm Des 2012; 18(8): 1084-97. [6] Ferro-Flores G, Ocampo-García BE, Melendez-Alafort L. Development of specific radiopharmaceuticals for infection imaging by targeting infectious micro-organisms. Curr Pharm Des 2012; 18(8): 1098-1106.

Molecular imaging is a fast growing field in biomedical research. The discovery, development and continual improvement of molecular probes are important for ongoing research efforts in molecular imaging. Human serum albumin (HSA) offers favorable charac-teristics and opportunities as a platform protein for molecular imaging probe discovery and optimization. It has many advantages, includ-ing alternation of biodistribution and pharmacokinetic properties of molecular imaging probes, enhancing the blood half-life of bio-molecules, and making these molecules multivalent, all of which make HSA a promising carrier for cancer-targeted imaging and therapy. Numerous studies have focused on the development and application of HSA-based cancer imaging and treatment. This review gives a brief account of albumin-based molecular probes, focusing on their applications in cancer molecular imaging, such as PET/SPECT, MRI and optical imaging.

Angiogenesis is necessary for tumor growth, without which a tumor can not grow beyond a few millimeters in diameter. This review summarizes the current status on the research of peptide Arg-Gly-Asp (RGD) and Arg-Arg-Leu (RRL) as well as its derivatives applied in tumor angiogenesis imaging and targeted therapy with single photon emission tomography (SPECT) and positron emissiontomography (PET). Peptide RGD sequence Arg-Gly-Asp targeted and combined to integrin αvβ3 which has been overexpressed on tumor endothelial cells and many different tumor cellsis a robust site for tumor angiogenesis molecular imaging and targeted therapy. The vari-ous derivatives of RGD were focused on optimizing its biological characteristics including affinity, targeting efficacy and pharmacoki-netics. The other alternative novel tumor angiogenesis molecular imaging agent is RRL peptide which targeted to tumor derived endothe-lial cells and then applied to visualize tumor angiogenesis with enhanced ultrasonic imaging, optical imaging and SPECT in animal. These novel peptide agents can have promising applications for tumor angiogenesis imaging and antiangiogenic tumor therapy.

Coronary artery disease (CAD) is the main cause of death and remains a major health problem worldwide. Myocardial perfu-sion imaging is a well established noninvasive method for assessing CAD. This review summarizes the development of various ra-diotracers for myocardial perfusion imaging, including single photon emission computed tomography (SPECT) perfusion imaging agents and positron emission tomography (PET) perfusion imaging agents and introduces novel basic research data related to this area. In addi-tion, the current state of the art in myocardial perfusion imaging agents and the future direction are discussed in this review.

Frequent overexpression of the folate receptor (FR) on a variety of tumor types and on activated macrophages makes this re-ceptor an interesting target for both imaging and therapy of cancer and inflammation. The FR is a glycosylphophatidylinositol-anchored protein that binds the vitamin folic acid with high affinity and internalizes it via endocytosis. In normal tissues and organs, FR-expression is restricted to only a few sites where it is confined to the luminal surface of polarized epithelia and hence does not have access to intra-venously administered folic acid conjugates. Thus, using folic acid as a molecular “Trojan horse” to deliver attached probes to the dis-eased tissue has emerged as a powerful strategy. A variety of folic acid radioconjugates for potential application in nuclear medicine have been developed and (pre)clinically evaluated during the last two decades. Herein we report on folate receptor targeted tracer design and in vitro/in vivo investigations using folic acid-targeted radioconjugates suitable for SPECT and PET imaging as well as for potential therapeutic purposes.

Hypoxic tissue exists in most of the solid tumors and hypoxia is a common character of these tumors. The existence of hy-poxic tissue in the tumor decreases the efficacy of radiotherapy and chemotherapy. Radiolabeled hypoxia markers have been developed to measure the hypoxic tissue together with non-invasive imaging techniques such as PET, SPECT, and PET/CT. This offers a conven-ient approach to delineate the tumor providing useful information for diagnosing cancer and guiding the treatment plan. Bioreducible or-ganic compounds have been developed as the hypoxia markers to probe tissue hypoxia noninvasively because they can be reduced and metabolized under hypoxic conditions; form adducts with cell components, and thus be trapped in the hypoxic tissue. These compounds include nitroimidazoles and other redox-sensitive compounds such as BnAO and ATSM. Different radionuclides have been used to label these compounds such as technetium-99m, iodine-123, fluorine-18, copper-64, etc. In addition, to detect hypoxia with endogenous hy-poxia markers such as carbonic anhydrase IX (CA IX) and hypoxia-inducible factor-1 (HIF-1), some radiolabeled tracers have also been developed. This article is an overview of the progress in this area in the past decade including the development of radiolabeled com-pounds for hypoxia detection and problems associated with the hypoxia marker development.

Infectious diseases remain a major health problem and cause of death worldwide. A variety of radiopharmaceuticals are used for the imaging of infections and inflammation in the practice of nuclear medicine. Long-term clinical use has shown that the majority of radiolabeled probes cannot distinguish between inflammation and infection. Gallium-67-citrate binds to bacteria, but also to proteins ac-cumulating at both sterile inflammation and bacterial infection sites. Other agents are used to interact with receptors or domains on circu-lating and infiltrating leukocytes or to label them directly. However, these probes cannot distinguish between infection and inflammation because they are not specific to infectious micro-organisms. This review examines the recent developments and applications of radiola-beled specific agents, such as antiviral drugs, antifungal, antibiotics and antimicrobial peptides, to visualize infectious foci by targeting viruses, fungi or bacteria.

Neurodegenerative diseases are some of the most fearsome illnesses, which include common disorders such as Alzheimer's and Parkinson's, and other rarer as Hungtinton's disease, spinocerebellar ataxia, prion diseases, and amyotrophic lateral sclerosis. In spite of the diversity in clinical manifestation, neurodegenerative disorders share some common features such as their appearance late in life, the progressive and chronic nature of the disease, the extensive neuronal loss and synaptic abnormalities and the presence of cerebral deposits of misfolded protein aggregates. Research over the past 10 years has provided evidence for a common mechanism of neurodegeneration in which the critical event is the misfolding, aggregation and accumulation in the brain of otherwise normal proteins [1]. These deposits are a typical disease signature and although in each disease the main protein component is different, they have similar morphological, structural and staining characteristics. One of the most active research areas that has contributed substantially to our current understanding of the molecular basis ofneurodegenerative diseases is the creation and development of diverse animal models to study them. The main goal of this special issue of Current Pharmaceutical Design is to summarize some of the key animal models and their important contributions for the study of neurodegenerative diseases. The first article by Rincon-Limas and colleagues [2] describe the importance of Drosophila melanogaster to model various aspects of neurodegenerative diseases, summarizing the many articles published using transgenic fly models of diverse neurodegenerative diseases. They also discuss the strengths and weaknesses of the use of flies to study human diseases. The article by Morley and colleagues [3] describes the senescence accelerated mouse to model various aspects of neurodegenerative diseases associated with aging, in particular Alzheimer&apos ;s disease. This article outlines the characteristics of the various senescence accelerated mice and discusses in detail the SAMP8 mice as a putative model for Alzheimer's disease. The article by Kitazawa and colleagues [4] provides a comprehensive overview of the manytransgenic mice models of Alzheimer's disease and the critical role these animals have played on understanding diverse aspects of the disease. They also discuss the limitations of transgenic mice and their importance for identification and testing of novel therapeutic approaches. The article by Moreno-Gonzalez and Soto [5] outlines the potential of studying the natural appearance of disease characteristics and processes in non-transgenic animals as a consequence of aging. The article summarizes many studies in which neuropathological abnormalities reminiscent of those observed in various neurodegenerative diseases have been reported to occur spontaneously in various non-human mammals. Finally, the article by Heuer and colleagues [6] describes the importance of primates as perhaps the closest model for the disease in humans. The overall conclusion of these articles is that animal models have played and will continue playing a crucial role to understand the pathogenesis of neurodegenerative diseases. Understanding the potential, strengths and weaknesses of each of these models is important to decide which model system provides the best advantage for specific studies. I hope this special issue will contribute to advance the science in the field of neurodegenerative diseases where effective treatments are still much needed. REFERENCES [1] Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nature Rev Neurosci 2003; 4: 49-60. [2] Rincon-Limas D, Jensen K, Fernandez-Funez P. Drosophila models of proteinopathies: the little fly that could. Curr Pharm Des 2012; 18(8): 1108-22. [3] Morley JE, Farr SA, Kumar VB, Armbrecht HJ. The SAMP8 mouse: A model to develop therapeutic interventions for Alzheimer's disease. Curr Pharm Des 2012; 18(8): 1123-30. [4] Kitazawa M, Medeiros R, LaFerla FM. Transgenic mouse models of Alzheimer disease: Developing a better model as a tool for therapeutic interventions. Curr Pharm Des 2012; 18(8): 1131-47. [5] Moreno-Gonzalez I, Soto C. Natural animal models of neurodegenerative protein misfolding diseases. Curr Pharm Des 2012; 18(8): 1148-58. [6] Heuer E, Rosen RF, Cintron A, Walker LC. Nonhuman primate models of alzheimer-like cerebral proteopathy. Curr Pharm Des 2012; 18(8): 1159-69.

Alzheimer's, Parkinson's, and Huntington's disease are complex neurodegenerative conditions with high prevalence character-ized by protein misfolding and deposition in the brain. Considerable progress has been made in the last two decades in identifying the genes and proteins responsible for several human ‘proteinopathies’. A wide variety of wild type and mutant proteins associated with neu-rodegenerative conditions are structurally unstable, misfolded, and acquire conformations rich in ß-sheets (ß-state). These conformers form highly toxic self-assemblies that kill the neurons in stereotypical patterns. Unfortunately, the detailed understanding of the molecu-lar and cellular perturbations caused by these proteins has not produced a single disease-modifying therapy. More than a decade ago, sev-eral groups demonstrated that human proteinopathies reproduce critical features of the disease in transgenic flies, including protein mis-folding, aggregation, and neurotoxicity. These initial reports led to an explosion of research that has contributed to a better understanding of the molecular mechanisms regulating conformational dynamics and neurotoxic cascades. To remain relevant in this competitive envi-ronment, Drosophila models will need to expand their flexible, innovative, and multidisciplinary approaches to find new discoveries and translational applications.

The senescence accelerate mouse P8 (SAMP8) is an excellent model of early learning and memory problems. A number of studies have shown that it has cholinergic deficits, oxidative damage, alterations in membrane lipids and circadian rhythm disturbances. The brains of the SAMP8 overproduce amyloid precursor protein (APP), amyloid-beta protein and have an increased physphorylation of tau. An antisense to APP has been developed that reverses the cognitive deficits and oxidative damage. This antisense represents a poten-tial treatment for Alzheimer's disease.

Alzheimer disease (AD) is the leading cause of dementia among elderly. Currently, no effective treatment is available for AD. Analysis of transgenic mouse models of AD has facilitated our understanding of disease mechanisms and provided valuable tools for evaluating potential therapeutic strategies. In this review, we will discuss the strengths and weaknesses of current mouse models of AD and the contribution towards understanding the pathological mechanisms and developing effective therapies.

Neurodegenerative diseases (NDs) are some of the most debilitating human illnesses. Research over the past 10 years has pro-vided evidence for a common mechanism of neurodegeneration in which the critical event is the brain accumulation of misfolded protein aggregates. Although it is well established that misfolded proteins play an important role in these diseases, the mechanisms by which they cause cellular and tissue dysfunction are still unknown. To understand the molecular basis of NDs and to develop therapeutic strategies against them, numerous transgenic rodent models have been produced, which reproduce some (but not all) of the features of these dis-eases. Importantly, some NDs are not exclusive to human beings, such as transmissible spongiform encephalopathies. Moreover, other diseases which are associated to aging (e.g. Alzheimer's disease) could be studied in aged mammals, which could reproduce the human disease in a more natural way. Although the usefulness of transgenic mice is unquestionable, the information obtained from natural non-transgenic models could be very valuable to fully understand the pathogenesis of these devastating diseases.

Nonhuman primates are useful for the study of age-associated changes in the brain and behavior in a model that is biologically proximal to humans. The Aβ and tau proteins, two key players in the pathogenesis of Alzheimer's disease (AD), are highly homologous among primates. With age, all nonhuman primates analyzed to date develop senile (Aβ) plaques and cerebral β-amyloid angiopathy. In contrast, significant tauopathy is unusual in simians, and only humans manifest the profound tauopathy, neuronal degeneration and cogni-tive impairment that characterize Alzheimer's disease. Primates thus are somewhat paradoxical models of AD-like pathology; on the one hand, they are excellent models of normal aging and naturally occurring Aβ lesions, and they can be useful for testing diagnostic and therapeutic agents targeting aggregated forms of Aβ. On the other hand, the resistance of monkeys and apes to tauopathy and AD-related neurodegeneration, in the presence of substantial cerebral Aβ deposition, suggests that a comparative analysis of human and nonhuman primates could yield informative clues to the uniquely human predisposition to Alzhei 's disease.

Engineering of Conotoxins for the Treatment of Pain Pp.4242-4253; Bodil B. Carstens, Richard J. Clark, Norelle L. Daly, Peta J. Harvey, Quentin Kaas and David J. Craik. Current Pharmaceutical Design, Vol. 17 (38), 2011. The figure 4 in the above stated publication was inadvertently published incorrectly owing to a production error. Below is the correct version with the legend reproduced for convenience. The electronic version of the article has already been corrected.