Current Pharmaceutical Design - Volume 12, Issue 30, 2006

This is the fourth issue of Current Pharmaceutical Design discussing applications of PET and SPECT in drug development. The initial issue (Vol. 6, No. 16, 2000) described methods for measuring the deposition, biodistribution and pharmacokinetics of drugs including their interactions with certain targets. The second issue (Vol. 8, No. 16, 2002) focused on the interface between nuclear medicine and molecular biology. A third issue (Vol. 10, No. 13, 2004) identified novel areas where molecular imaging could contribute to drug design: anti-angiogenic therapy, modulation of programmed cell death, suppression of beta-amyloid plaque formation, inhibition of cerebral acetycholinesterase and of P-glycoprotein-mediated drug transport in the blood-brain barrier, downregulation of beta-adrenoceptors by antidepressants. The current issue gives an overview of novel targets within the human brain for which radioligands have recently been developed. Drs. Ding, Lin and Logan [1] from Brookhaven National Lab (Upton, NY, USA) describe the efforts of several research groups to visualize the cerebral norepinephrine transporter (NET). It has proven quite difficult to develop suitable radioligands for this particular target, although dopamine and serotonin transporter ligands are readily available. The development of (S,S)-[11C]methylreboxetine is a breakthrough, since this compound displays a much greater in vivo selectivity and specifity than any other existing NET radioligand. Since the writing of this review, a fluorinated derivative of reboxetine has been reported to show even better properties1. The availability of (S,S)-[11C]methylreboxetine may allow researchers to probe the contribution of the NET system to specific brain disorders, such as attention-deficit hyperactivity disorder (ADHD), substance abuse, Alzheimer’s disease and Parkinson’s disease, and to monitor NET occupancy during treatment with antidepressant drugs. Dr. De Vries [2] from the University of Groningen (The Netherlands) focuses on another difficult target. Expression of cyclooxygenase-2 (COX-2) within tissues is transiently induced during inflammation and in brain disorders like Alzheimer's disease and Parkinson's disease. The enzyme is also overexpressed in a variety of tumors, and related to angiogenesis, tissue invasion, metastasis and apoptosis. A noninvasive method to monitor COX-2 expression may provide novel insights in the role of COX-2, particularly within the CNS where repetitive sampling is not possible. Two radiolabeled COX-2 inhibitors show specific binding within brain, but the high lipophilicity of these compounds results in a high background signal. However, it is possible to study the effects of COX-2 inhibitors on blood flow, glucose metabolism and apoptosis with PET. Drs. Hashimoto and Ishiwata [3] from Chiba Graduate University of Medicine and the Tokyo Metropolitan Institute of Gerontology (Japan) discuss the application of sigma receptor ligands as therapeutic drugs and as radiopharmaceuticals. Sigma receptors are novel targets for the therapeutic treatment of schizophrenia, depression, cognitive impairment, stroke-induced ischemia, and cocaine addiction. Sigma-2 agonists are novel therapeutic drugs for the treatment of cancer. Radioligands for sigma-1 and sigma-2 receptors have been developed by various research groups. PET and SPECT studies with these radioligands may provide insight in the role which sigma receptors play in pathophysiology. Such studies also allow measurement of sigma receptor occupancy by therapeutic drugs, and will be of prognostic relevance in cancer patients. Drs. Horti and Villemagne [4] from Johns Hopkins Medicine (Baltimore, USA) and the University of Melbourne (Australia) review the development of radioligands for imaging of nicotinic acetylcholine receptors (nAChR) within human brain. For a variety of reasons, cerebral nAChR are a difficult target. They are expressed at much lower densities than e.g. dopamine receptors. First-generation ligands (epibatidine analogs) were very toxic. Second-generation radioligands (A-85380 analogs) showed a better toxicity profile but slow brain kinetics and moderate signal-to-noise ratios. Ligands with better kinetics have been developed but not yet characterized in vivo. If they prove suitable, such ligands can be used to elucidate the role of nAChR in (patho)physiology, to monitor response to cholinergic drugs in Alzheimer's disease and to correlate therapeutic response to nAChR occupancy. Finally, Dr. Eckelman [5] from Molecular Tracer, LLC (Bethesda, MD, USA), reviews imaging studies on muscarinic receptors (mAChR) within the central nervous system....

The involvement of the norepinephrine transporter (NET) in the pathophysiology and treatment of attention deficit hyperactivity disorder (ADHD), substance abuse, neurodegenerative disorders (e.g., Alzheimer's disease (AD) and Parkinson's disease (PD)) and depression has long been recognized. However, many of these important findings have resulted from studies in vitro using postmortem tissues; as of now, these results have never been verified via in vivo methods because brain imaging of NET in living systems has been hampered due to the lack of suitable radioligands. The fact that all three monoamine (dopamine, norepinephrine, and serotonin) transporters (DAT, NET and SERT) are involved in various neurological and psychiatric diseases further emphasizes the need to develop suitable NET ligands so that researchers will be able to probe the contributions of each monoamine transporter system to specific CNS disorders. In this review article, the design and biological evaluation of several radioligands for imaging the brain NET system with PET are discussed. Based on these characterization studies, including C-11 labeled desipramine (DMI), 2-hydroxydesipramine (HDMI), talopram, talsupram, nisoxetine (Nis), oxaprotiline (Oxap), lortalamine (Lort) and C-11 and F-18 derivatives of reboxetine (RB), methylreboxetine (MRB) and their individual (R, R) and (S, S) enantiomers, in conjunction with studies with radiolabeled 4-iodo-tomoxetine and 2-iodo-nisoxetine, we have identified the superiority of (S, S)-[11C]MRB and the suitability of the MRB analogs as potential NET ligands for PET. In contrast, Nis, Oxap and Lort displayed high uptake in striatum (higher than thalamus). The use of these ligands is further limited by high non-specific binding and relatively low specific signal, as is characteristic of many earlier NET ligands. Thus, to our knowledge, (S, S)-[11C]MRB remains by far the most promising NET ligand for PET studies.

Cyclooxygenase is an enzyme that catalyzes the first two steps in the biosynthesis of prostanoids. The constitutively expressed isoform COX-1 is regarded as a housekeeping enzyme that is responsible for the normal production of prostanoids. The inducible isoform COX-2, on the other hand, is transiently induced during inflammation by various stimuli. Increasing evidence has shown that COX-2 is not only implicated in inflammation but also in oncogenesis. Overexpression of COX-2 has been observed in a variety of tumors. Prostaglandins produced by COX-2 affect important processes in carcinogenesis, including angiogenesis, tissue invasion, metastasis and apoptosis. Several studies indicate that COX-2 is also involved in neurological disorders, like Alzheimer's disease, Parkinson's disease and ischemia, where COX-2 overexpression leads to neurotoxicity. Many aspects of the role of COX-2 in (patho)physiology, however, remain unclear. At present, COX-2 expression is determined by ex vivo laboratory analysis, but the results could be greatly affected by the instability of COX-2 mRNA and protein and by sampling errors. A noninvasive imaging method to monitor COX-2 expression, like positron emission tomography (PET) or single photon emission computed tomography (SPECT), could overcome this complication and may provide novel insights in the role of COX-2, especially in neurological disorders where repetitive sampling is not possible. Such a technique could also be applied to the in vivo evaluation of novel selective COX-2 inhibitors and in dose-escalation studies. This review will present an overview of the developments in the recently emerging field of COX-2 imaging.

Sigma receptors are classified into sigma1 and sigma2 subtypes. These subtypes display a different tissue distribution and a distinct physiological and pharmacological profile in the central and peripheral nervous system. The characterization of these subtypes and the discovery of new specific sigma receptor ligands demonstrated that sigma receptors are novel targets for the therapeutic treatment of neuropsychiatric diseases (schizophrenia, depression, and cognition), brain ischemia, and cocaine addiction. Furthermore, imaging of sigma1 receptors in the human brain using specific PET radioligands has started. In addition, the two sigma receptor subtypes are also expressed on tumor cells, where they could be of prognostic relevance. The ability of sigma2 receptor agonists to inhibit tumor cell proliferation through mechanisms that might involve apoptosis, intracellular Ca2+, and sphingolipids has promoted the development of sigma2 receptor agonists as novel therapeutic drugs for treating cancer. Consequently, sigma2 receptor ligands have been demonstrated to be potentially useful tumor imaging ligands. In this article, we focus on the sigma receptor ligands as therapeutic agents and as radiopharmaceuticals.

Neuronal nicotinic acetylcholine receptors (nAChRs), ubiquitously distributed in the human brain, are implicated in various neurophysiological processes and in the pathophysiology and/or treatment strategies of Alzheimer's and Parkinson's diseases, Tourette's syndrome, epilepsy, schizophrenia, depression, and anxiety, as well as being particularly affected in tobacco dependence/withdrawal. In the past two decades, researchers have developed an extensive series of radioligands for the assessment of nAChRs in vivo through emission tomography, PET and SPECT. Several radioligands, derivatives of A-85380: 2-[18F]FA, 6-[18F]FA and 5-[123I]IA, are now being employed for the evaluation of nAChR in humans with PET and SPECT. Displaying better imaging properties than 11C-nicotine and a better toxicity profile than epibatidine analogs, they have allowed quantification of thalamic nAChR in the human brain. Nevertheless, A-85380 derivatives still exhibit slow brain kinetics and a moderate signal-to-noise ratio. Current research efforts on the part of PET/SPECT radiochemists, therefore, have focused on development of new, highly specific and highly selective nAChR radioligands with improved brain kinetics that are able to localize high-affinity nAChRs in vivo. Key examples of new PET/SPECT ligands that are derived from several different structural classes are discussed along with a review of their chemical as well as their in vitro and/or in vivo properties. In particular, new PET nAChR radioligands will be examined that either present faster brain kinetics allowing simple and reliable quantification approaches or higher binding potentials suitable for the evaluation of extrathalamic nAChR.

The development of receptor-binding radiotracers has evolved from a goal of high affinity compounds to give high target to non target ratios to compounds of slightly lesser affinity so that they can reach either steady state after bolus injection or equilibrium after infusion. The other important advance is the ability to measure endogenous neurotransmitter, using various lower affinity muscarinic acetylcholine receptor radioligands. There have been a number of clinical studies that elucidated the mechanism of action of new pharmaceuticals in vivo using external imaging. These include studies of drug interaction of olanzapine, risperidone, clozapine, donepezil, and phenserine with the muscarinic receptor. There have been fewer studies monitoring the effect of therapy in Alzheimer's disease, but those pilot studies give great hope that monitoring therapy is a real possibility. Radioligands for the muscarinic receptor, for ACh esterase, and to measure the concentration of acetylcholine have now been developed, A number of studies in small populations have identified changes in mild to moderate Alzheimer's disease and, perhaps more importantly, changes in radioligand binding have been identified in clinically normal subjects genetically predisposed to Alzheimer's disease by virtue of the epsilon 4+ variant of the APOE gene. Large scale clinical studies are now needed to delineate the true value of these radiotracers in clinical situations. PET and SPECT imaging hold the promise of monitoring the effect of pharmaceuticals in a wide variety of diseases using non-invasive external imaging of the muscarinic cholinergic system.

Mammalian reproduction is a complex physiological process involving a tightly regulated hypothalamicpituitary- gonadal axis and the integration of a diverse array of molecular signals. Oral contraceptives (OCs) were introduced over 40 years ago and have evolved over the years through the discovery of new estrogens and progestins, the development of progestin-only pills and the reduction of the estrogen content in combined OCs. Despite the developments that improved the safety profile of current OCs, adverse metabolic and vascular effects caused by the estrogen component and possible neoplastic effects of OCs remain and, thus, necessitate efforts to develop newer, possibly non-steroidal and non-hormonal, contraceptives. Recent advances in our understanding of ovarian endocrinology, coupled with molecular biology and transgenic technology, have enabled identification of several factors that are functionally critical in the regulation of female fertility. Progress in the area of female reproduction is showing great promise for identifying new contraceptive drug targets. In this article, the authors review the field of female contraception with emphasis on novel targets involved in reproductive function and identified through genomics and proteomics. In addition, the usefulness of these targets for contraception purposes will be discussed.

Immunoglobulin E (IgE) plays a central role in the development of allergic diseases. In sensitized individuals, IgE antibodies bind to receptors on mast cell and basophil surfaces, releasing preformed and newly generated mediators that initiate an immunologic cascade and inflammatory symptoms. Omalizumab (Xolair®) is a humanized monoclonal antibody designed to bind specifically to IgE. It was approved by the United States Food and Drug Administration in 2003 for the treatment of patients with moderate-to-severe persistent asthma that is inadequately controlled with inhaled corticosteroids (ICS) and who have a positive skin test or in vitro reactivity to a perennial aeroallergen. In clinical trials in such patients, omalizumab reduced the incidence of asthma exacerbations, severe exacerbations, the use of rescue medication, and improved both symptoms and quality of life (QOL).

The rising number of elderly people has a major impact on healthcare systems. Advancing age is a risk factor for the development of cardiovascular disease (CVD), which represents a major global healthcare problem. The clinical efficacy and safety of lipid lowering treatment (especially statins) is well established following a series of large-scale, randomised controlled trials, which mainly recruited patients under the age of 70 years. Subgroup analyses together with the findings of trials involving sufficient numbers of elderly participants, such as the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) and the Heart Protection Study (HPS) offer a basis for considering statin therapy in this population. Furthermore, since this population is at greater absolute risk of CVD, substantial benefits from adequate treatment may be anticipated. However, underevaluation and undertreatment appear to be common in the elderly. In this review, we provide a survey of potentially modifiable cardiovascular risk factors in association with old age, and discuss the relevant findings of large-scale end-point clinical studies as well as major considerations regarding lipidlowering treatment in this population. It is concluded that the decision whether to treat hypercholesterolaemia in the elderly is currently individualised, depending upon the degree of risk, general health, willingness to receive treatment and financial concerns. Further, prospective randomised trials are required to guide physicians towards an effective management of older individuals at increased atherosclerotic risk.