Current Pharmaceutical Design - Volume 7, Issue 18, 2001

Positron Emission Tomography (PET) has the potential to improve efficacy of established and novel cancer therapies and to assist more rapid and rational progression of promising novel therapies into the clinic. This is due to PET's unrivalled sensitivity and ability to monitor the pharmacokinetics and pharmacodynamics of drugs and biochemicals radiolabelled with short -lived positron emitting radioisotopes. PET is a multidisciplinary science which employs chemists, biologists, mathematicial modellers, pharmacologists as well as clinicians. Clinical research questions in oncology determine the methodological challenges faced by these other disciplines. Within this context we focus on the developments of the radiolabelled compounds that have underpinned the clinical work in oncology for monitoring tumour and normal tissue pharmacokinetics, assessment of tumour response, cell proliferation, gene expression, hypoxia, multidrug resistance and status of receptors on tumours.

Enzymes, the expression products of transferred or native genes, offer unique windows of opportunity for clinical diagnosis and therapy. Although some expression products can be monitored in plasma, nuclear medicine imaging (SPECT and PET) offers the unique ability to selectively measure the intensity and regional / spatial distribution of gene expression both in vivo, in situ. Importantly, the superior sensitivity and moderate spatial resolution of the nuclear techniques also enable in vivo kinetic characterization of enzyme-substrate interaction. Indeed, the non-invasive, whole-body assessment of gene expression can only be achieved through imaging techniques. Given today's technology, nuclear imaging techniques uniquely provide the necessary sensitivity required to evaluate the success of the gene delivery and expression (transcription and translation), and to detect unwanted expression by non-target tissues.Enzymes are a special class of proteinacious gene expression products that selectively bind specific substrates for the purpose of molecular biotransformation rather than for signal transduction. In general, enzymes have received much less attention for imaging than receptors and antibodies, despite the enzymes' high substrate specificity and the potential for kinetic evaluation. Enzymes are attractive targets for diagnostic imaging and radioisotope radiotherapy because they convert multiple molecular copies of the substrate (radiotracer) per molecule of enzyme, thereby greatly increasing the ultimate sensitivity relative to the sensitivity offered by receptors that bind with 1:1 stoichiometry. Not surprisingly, enzymes have been the preferred molecular targets to date for scintigraphic imaging of gene therapy.This overview describes opportunities and advances in the utilization of radiolabelled nucleosides and nucleoside bases for imaging in gene therapy, with emphasis on the exploitation of enzyme systems for scintigraphic imaging of gene expression in gene therapy of cancer. Herpes simplex virus type-1 thymidine kinase and bacterial / fungal cytosine deaminase are discussed within the context of gene therapy issues such as gene vectors for targeting and delivery, the bystander effect, and radionucleoside delivery. The utilization of nucleosides as markers of tissue proliferation is discussed with respect to selected enzyme targets.

A basic problem in the discovery and development of novel drugs to be used in the treatment of neurological and psychiatric disorders is the absence of relevant in vitro or in vivo animal models that can yield results which can be extrapolated to man. Drug research now benefits from the fast development of functional imaging techniques such as positron emission tomography (PET) which trace radiolabelled molecules directly in the human brain. PET uses molecules that are labelled with short-lived radionuclides and injected intravenously into experimental animals, human volunteers or patients.The most frequent approach is to study how an unlabelled drug inhibits specific binding of a well characterised selective PET radioligand. The alternative direct approach is to radiolabel a new potential drug and to trace its uptake, anatomical distribution and binding in brain. Furthermore, the effects of a novel drug on physiological-biochemical parameters, such as glucose metabolism or blood flow, can also be assessed. The demonstration of quantitative relationships between drug binding in vivo and drug effects in patients is used to validate targets for drug action, to correlate pharmacological and physiological effects, and to optimise clinical treatment.

The only bromine and iodine radioisotopes worth using in PET or SPECT in vivo investigations during the development of a new drug are 76Br and 123I. It is most of the time impossible to isotopically label a drug with 76Br or 123I since the occurrence of drugs having a bromine or an iodine atom within their chemical structure is quite limited. However, by using specific radiobrominated or radioiodinated probes, it is possible to study in vivo the potential interaction of a drug with biochemical processess such as blood flow, glucose consumption, protein synthesis or cell proliferation and neurotransmission. Radiobrominated and radioiodinated probes have been described mainly for assessing cell proliferation. For imaging various classes of specific binding sites involved in neuronal or hormonal transmission, a great number of radiohalogenated ligands have been proposed and validated. The two-steps strategy consists of performing an “in vivo assay” by using first of all, one of these specific radio-brominated / -iodinated ligands (or probes) for targeting specific binding sites (receptor, transporter, enzymes) and in a second step by assessing the interaction of the cold drug on the binding of these probes. This indirect observation of drug-receptor (transporter, enzyme) occupancy allows predicting response, optimum dose and optimum scheduling. The most important radiobrominated and radioiodinated ligands specific for dopaminergic, serotoninergic, cholinergic and gabaergic binding sites and their application in drug development processes are reviewed.

Radiotracer imaging studies performed on animals have the potential to play a major role in pharmaceutical development, pharmacology studies and basic biochemistry research. Recent developments in instrumentation and imaging metho- dology make it possible to image and quantify the kinetics of radiolabelled pharmaceuticals in a wide range of animal models from rodents to non-human primates. This article reviews the developments which have led to the current state-of-the-art, including advances in detector technologies, image reconstruction and tracer kinetic modelling. The practical issues specific to animal imaging studies are also discussed. With appropriate instrumentation and rigorous methodology, quantitative pre-clinical imaging has an important role to play in drug development.