New-generation radiotracers for nAChR and NET
Introduction
Positron emission tomography (PET) uses radiotracers labeled with short-lived positron emitting isotopes, such as carbon-11 (half-life is 20 min) and F-18 (half-life is 110 min), to track biochemical transformations, changes brought about by disease, as well as the movement of drugs in the living human and animal body. Modern PET research is enriched and strengthened from the integration of many disciplines; however, it is advances in radiotracer chemistry that have played the pivotal role in driving the field in new directions in studies of human physiology. At the heart of this development is synthetic chemistry directed to the rapid incorporation of simple short-lived precursor molecules into organic compounds that can be used to map specific biochemical processes and the movement of drugs in living systems. In this presentation, we will first focus on the development of nAChR radiotracers. We will present how we characterize radiotracers in animals, how we apply tracers to study neuroscience and how we translate a promising radioligand from preclinical investigation in primates to clinical research in humans. We will also touch upon the safety assessment of novel, high-specificity, low-mass radiotracers for use in humans. We will also present some of our recent progress in the development of NET radiotracers, including a discussion of the relationship between the behavior of chemical compounds in vivo and their in vitro properties such as log P and affinities. We will conclude with a perspective on the current scientific and infrastructure needs to facilitate the design and development of new radiotracers and their translation into practice of health care.
Section snippets
Research design and methods
Our overall plan is to develop novel radioligands for imaging various central nervous system (CNS) molecular targets in vivo with PET and to apply these radioligands to examine their roles in the living systems. This involves the development and translation of a lead tracer from the preclinical stage in nonhuman primates through its full characterization in human subjects, including healthy controls and subjects with various CNS disorders.
Examples for development of a new generation of radiotracers for neurotransmitter systems
The development of radiotracers for imaging neurotransmitter systems (including their receptors, their plasma membrane and vesicular transporters, the enzymes which synthesize and degrade them and the processes involved in signal transduction) has dominated radiotracer research. The reasons for this are obvious when one considers that mental processes are driven by the complex interplay of neurotransmitter systems and that their disruption underlies many diseases of the CNS [8]. In the
Outlook
Despite the increasing reliance of the biomedical sciences on imaging, the development of new radiotracers remains a slow process. Even the familiar radiopharmaceuticals that are the backbone of imaging sciences are the product of enormous effort and even serendipity. Yet the value of radiopharmaceuticals in almost every area of clinical research is of such enormous societal importance that it justifies a more focused effort in identifying the impediments and in setting scientific and medical
Long-term needs
The human body presents a complex set of barriers, including the BBB, plasma protein binding, sequestration in cells, nonspecific tissue binding, metabolism, etc., which compete with radiotracer delivery to the target organ. Despite decades of experience, our ability to predict which chemical compounds would have suitable bioavailability, specificity and kinetics required to image and quantify specific molecular targets in the brain and other organs remains limited. As a result, there are a
Acknowledgment
Much of this work was carried out at Brookhaven National Laboratory under contract DE-AC02-98CH10886, with the US Department of Energy and supported by its Office of Biological and Environmental Research and also by the National Institutes of Health (National Institute for Biomedical Imaging and Bioengineering EB002630 and National Institute on Drug Abuse DA-06278) and Office of National Drug Control Policy. We are also thankful to J. Logan, K.-S. Lin, D. Pareto, A. Biegon, H. Benveniste, G.-J.
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