Current Pharmaceutical Design - Volume 6, Issue 16, 2000

Positron Emission Tomography (PET) is an imaging modality which can determine biochemical and physiological processes in vivo in a quantitative way by using radiopharmaceuticals labeled with positron emitting radionuclides as [sup11 ]C, [sup13 ]N, [sup15 ]O and [sup18 ]F and by measuring the annihilation radiation using a coincidence technique. This includes also measurement of the pharmacokinetics of labeled drugs and the assessment of the effects of drugs on metabolism. Because only very low amounts of the radiolabeled drug have to be administered, far below toxicity levels, human studies can be carried out even before the drug is entered in Phase I. Such studies can provide cost-effective predictive toxicology data and information on the metabolism and mode of action of drugs. PET is also very useful to study the metabolic consequences of gene expression or gene defects. In the last decade many genetically engineered small animal models have been developed. The study of these animals with high resolution small animal PET cameras provides new opportunities in drug development. Especially valuable is the contribution of PET to bridge the gap between molecularbiology,understanding of pathology and to the design of a new generation of drugs.

Many physiological and biochemical measurements can be performed noninvasively in humans with modern imaging techniques like magnetic resonance imaging (MRI), positron emission tomography (PET) or single-photon emission computed tomography (SPECT). This review focuses on the monitoring of drug-receptor interactions in patients and healthy volunteers with PET. Such studies depend on the availability of a suitable radioligand; they are already possible for classical and atypical neuroleptics, anxiolytics, antidepressants, anticholinergics, antihistamines, antiepileptics, beta-blockers and hypnotic drugs. In Phase I-II human studies, measurements of plasma pharmacokinetics can be combined with images of receptor occupancy and be quantitatively related to pharmacologic effects which are induced in the same subjects. Optimal dosing schedules can be defined and valuable information for the design of Phase III studies can be acquired. Moreover, the effect of interventions (e.g. change of dose, additional medication) can be predicted. Medical imaging techniques will play an increasing role in clinical pharmacology and allow well-informed go/no-go decisions in future drug development.

Monoamine transporters are proteins mainly located on nerve terminals of dopaminergic, noradrenergic and serotonergic neurons. They are members of a larger sodium dependent transporter family and represent a major mechanism terminating the action of released neurotransmitter in the synaptic cleft. In addition to being important target molecules for many antidepressive drugs and substances of abuse, transporter proteins are good markers for the integrity of monoaminergic innervation. Therefore, there is a growing interest for in vivo imaging studies using positron emission tomography (PET) or single photon emission computed tomography (SPECT) and ligands selective for monoamine transporters. In this review, the use of monoamine transporter ligands (or tracers) for imaging studies of cocaine dependence, neurodegenerative diseases and mechanism of antidepressant drug action is discussed, with special focus on the use of PET for evaluating possible new pharmacological innovations.

Positron emission tomography (PET) is currently the most useful imaging technique for noninvasive measurement of drug pharmacokinetics regionally in a variety of tissues. Over the past decade, PET measurements have provided many critical insights about the tissue distribution of several classes of drugs; neuroleptics, antimicrobials, antineoplastics, etc. PET measurements can be performed after any route of drug administration, intravenous, inhalation or oral, however, intravenously administered drugs have been the most extensively evaluated. Studies of orally administered drugs are clearly of great interest; however, formulation issues have precluded widespread applications in these areas. In this report, we discuss the unique problems associated with studying orally administered drugs and review the results of recent studies performed in our laboratory.

Drug biodistribution is often secondary to drug action. However, drugs that have a topical action and are deposited into the airway by inhalation are dependent on effective deposition at the intended site of action. Measurement of the distribution of such drugs in the airway is a useful tool. Distribution data can help to interpret clinical results, to evaluate products relative to each other, to optimize a new drug formulation, and to choose effective drug delivery methods. Imaging of radiotracers is the only means available to measure drug deposition throughout the lungs, nasal passages, and sinuses. There are several approaches to imaging drug deposition. Planar imaging has been the most used method, but SPECT and PET imaging are beginning to be applied effectively. The properties of non-drug tracers, labeling of drugs, evaluation of distribution patterns, and quantification of deposited drugs are important issues that have been addressed. Imaging has been shown to be a powerful technique to evaluate and to speed development of inhaled drugs. This review explores the most recent advances and issues with an emphasis on drug development.

Chemotherapeutic treatment of cancer patients is often unsuccessful, due to the involvement of various mechanisms, leading to multidrug resistance (MDR). In this review, I describe the mechanisms involved in MDR. Furthermore, results obtained by imaging of P-glycoprotein (P-gp) and the multidrug resistance associated protein (MRP) are reviewed.Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are unique techniques to study P-gp- and MRP-mediated transport. The radiopharmaceutical 99mTc-sestamibi is a substrate for both P-gp and MRP. This tracer has been used for tumor imaging in clinical studies, and to visualize blockade of P-gp mediated transport after modulation of the P-gp pump. Other 99mTc-radiopharmaceuticals such as 99mTc- tetrofosmin and several 99mTc-Q-complexes are also substrates for P-gp. Until now, for these compounds only results from in vitro and animal studies are available. For quantification of P-gp mediated transport with PET in vivo, several agents, such as [11C]colchicine, [11C]verapamil and [11C]daunorubicin have been evaluated. In vivo results suggest that these radiopharmaceuticals can be used to image P-gp function in tumors. 124I and 76Br radiolabeled doxorubicin analogues are also useful to examine P-gp mediated transport. Leukotrienes are specific substrates for MRP. Therefore, N-[11C]acetyl-leukotriene E4 provides the opportunity to study MRP function non-invasively. Results obtained with this radiopharmaceutical in MRP2 mutated GY/TR- rats indicate visualization of MRP-mediated transport. This tracer enables to study MRP transport function abnormalities in vivo such as in Dubin-Johnson patients, who are MRP2 gene deficient. In conclusion, it is feasible to study the functionality of MDR transporters in vivo, both with SPECT and with PET. Such imaging techniques may become an important factor in the development of novel chemotherapeutic drugs.

Liposomes, that are biodegradable and essentially non-toxic, can encapsulate both hydrophilic and hydrophobic materials, and are utilized as drug carriers for drug delivery systems (DDS). Recent progress in gene technology provides a novel modality of therapy for various diseases with a variety of newly-developed cationic liposomes. Delivery of agents to the reticuloendothelial system (RES) is easily achieved since most conventional liposomes are trapped by the RES. For the purpose of delivery of agents to target organs other than RES, long-circulating liposomes have been developed by modifying the liposomal surface. Understanding of the in vivo dynamics of liposome-carried agents is required to evaluate the bioavailability of drugs encapsulated in liposomes. In this review, we focus on the in vivo trafficking of liposomes visualized by positron emission tomography (PET) and discuss the characteristics of liposomes that affect the targeting of drugs in vivo.