Positron emission tomographic imaging in drug discovery

Highlights

• PET imaging accelerates the selection of drug candidates during the early stages of development.

• The estimation of receptor occupancy in the brain is one of the most important applications of PET.

• PET is also widely used in pharmacokinetics, biodistribution and treatment monitoring.

• There are several applications of PET imaging in oncological and cardiological drug discovery.

Abstract

Positron emission tomography (PET) is an extensively used nuclear functional imaging technique, especially for central nervous system (CNS) and oncological disorders. Currently, drug development is a lengthy and costly pursuit. Imaging with PET radiotracers could be an effective way to hasten drug discovery and advancement, because it facilitates the monitoring of key facets, such as receptor occupancy quantification, drug biodistribution, pharmacokinetic (PK) analyses, validation of target engagement, treatment monitoring, and measurement of neurotransmitter concentrations. These parameters demand careful analyses for the robust appraisal of newly formulated drugs during preclinical and clinical trials. In this review, we discuss the usage of PET imaging in radiopharmaceutical development; drug development approaches with PET imaging; and PET developments in oncological and cardiac drug discovery.

Introduction

The process of developing a new drug is expensive and lengthy. It has been estimated that the usual duration to advance a novel drug formulation from its conception to distribution in the market is 10 years and the projected cost is ~US$1.4 billion.1, 2 A longitudinal study on the length of drug development from 2000 to 2009 revealed that the average time taken for developing a new drug for CNS diseases is around 10 years. The same study showed the time of progression to be 5.1 years for antiviral drugs against AIDS and 7.6 years for anti-neoplastic drugs.³ This is a significant burden that not only weighs down the pharmaceutical industry, but also impacts an entire society. Although over the past two decades an increasing number of druggable targets have been identified as a result of rapid advancements in molecular biology, the number of approved drugs has not similarly increased.⁴ In addition, the development of new drugs for CNS disorders is imperative in the face of the growing incidence of such disorders, but hampered by our inability to fully map the progression of certain diseases. Reduced efficacy in drug development is also the result of our poor understanding of preclinical models.⁵ Moreover, the advancement of a CNS drug has several inherent impediments, such as inadequate access to the target organ, difficulties crossing the blood–brain barrier (BBB),⁶ and the challenges of being directly quantified in the brain. As a result of such issues, the typical cost of drug discovery is increasing and is likely to continue to do so. Consequently, approaches to expedite the drug discovery process and curb the rise in costs are being pursued.

The drug discovery process comprises several phases. Upon completion of the research phase of drug discovery, approval to examine new drug molecules in clinical subjects is acquired and a multistep clinical examination begins.⁷ The key intention of Phase I clinical trials is to assess drug safety in humans. It is also necessary to test a range of drug doses both above and below its intended dose, and to confirm that the drug candidate is well tolerated at its effective dosage. In this phase, the selected subjects are predominantly healthy volunteers (particularly in oncology). A focused patient population is required for Phase II clinical trials, during which the primary objective is to validate the safety and efficacy of the drug at its effective dose in the patient group. It is imperative to have positive data from Phase II trials before proceeding to the vital Phase III trials, the pivotal goal of which is to discern whether the new drug treatment can bring about considerable value and assess how the new formulation fares in relation to current drugs for the same disease.⁸ The length of the preclinical phase can change according to the diseases for which the drugs are purposed. Similarly, the duration of the clinical trial, inclusive of the approval steps, differs among the various drug categories.

It is anticipated that different imaging modalities, such as PET, could make an indispensable contribution to speed up the drug discovery process.⁹ Molecular imaging modalities could help in making decisions on effective dose administration and patient selection,¹⁰ and could also offer evidence regarding drug–target interactions in Phase I and phase II trials.¹¹ By using molecular imaging techniques properly, the pharmaceutical industry can identify the leading compound in early stages. Compounds that do not successfully display qualified activity during the preliminary stages can be discarded, and the candidates that demonstrate substantial activity can be accelerated for further development. Using this approach, the drug discovery process could become more cost effective and less painstaking.

A relevant and non-invasive functional imaging technique that is applied widely in the clinic is PET imaging. In PET imaging, a biologically active molecule is labeled with a positron-emitting radiotracer. Ultimately, this analytical technique allows for the visualization and quantification of biochemical and physiological processes in vivo, and is predominantly used in neurology, oncology, and cardiology.¹² The versatility of PET imaging gives it an edge over other functional imaging techniques. A diverse range of positron-emitting radionuclides, such as fluorine-18 (¹⁸F), carbon-11 (¹¹C), nitrogen-13 (¹³N), and oxygen-11 (¹¹O) are accessible. Moreover, owing to the distinct and variable characteristics of radionuclides, it is possible to select from a broad choice of radionuclides to label a wider range of biologically relevant compounds.² Table 1 presents selected different ¹¹C and ¹⁸F radioligands used for brain imaging.

As a marker of inflammation, translocator protein (TSPO), which is situated on the outer mitochondrial membrane, is upregulated on microglial cells.¹³ Neuroinflammation is characteristic of various neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), and can result in neuronal impairment. Although the PET tracer, [¹¹C](R)-PK 11195, has been used as a selective antagonist for TSPO,¹⁴ it has several limitations, such as comparatively low brain permeability and enhanced lipophilicity, causing it to bind strongly to hydrophobic macromolecules. The dopamine and serotonin (5-HT) receptors and transporters are targets implicated in PD among other brain pathologies.5, 16 Among the tracers aimed at these targets, [¹¹C]SCH 23390, [¹¹C]Raclopride, [¹⁸F]Fallypride and [¹⁸F]FE-PE2I17, 18, 19 are well-established ones used to quantify parameters defining pharmacodynamic effects in response to drug treatment.²⁰ Although antagonists for neuroreceptors have been primarily utilized as PET ligands, the usage of agonists forms a growing body of research be because they bind preferentially to the high-affinity state of the receptors.²¹ Similar to PD, numerous radiotracers have been developed for PET imaging of AD pathology. Amyloid β (Aβ)-directed radiotracers, such as the pioneering [¹¹C]PIB and the further optimized [¹¹C]AZD2184, and tau-targeted tracers, such as [¹¹C]PBB3, show potential for marking their respective target biomolecules with high affinity and could provide a base for further improvement of their characteristics.²²

PET imaging enables novel ‘precision pharmacology’, through which answers to whether new drugs are delivered to target tissues specifically in biologically effective dosages can be derived. This could significantly contribute to current understanding of drug discovery and development.²⁰ Given the burgeoning costs associated with the clinical developmental stage of a drug, a well-planned experiment can address vital queries during the early stages when fewer human subjects are required, paving the way for more assertive and economic decision-making. Thus, PET imaging could yield additional significance in drug discovery, because the data obtained are translatable from bench to bedside. Such translatability is important for improving the efficiency of drug development and for applying it in a clinical setting. Moreover, it ensures that the costs of evaluating and advancing drugs in disease treatment are minimized.

The main application of PET in drug discovery is to evaluate receptor occupancy over a range of dosages, thus making it useful to ascertain the optimal dosage of the drug.²³ Moreover, PET can be used to study drug PK, biodistribution, target validation, and disease monitoring.24, 25 It also aids our understanding of several important parameters, including the identification of possible drug metabolism its early stages of development, and the binding between the labeled radiometabolites and their respective receptors.²⁶ PET imaging also provides important information on whether the radiometabolites are capable of crossing the BBB.²⁷ The slow metabolism of the radiotracers suggests a long half-life and a comparatively high plasma concentration of the drug, which then offers valuable knowledge of the approximate dosage required for patients. Furthermore, PET is beneficial for selecting highly responsive patient populations for clinical trials and monitoring patient pathology in a longitudinal manner after drug treatment. This is because, through PET imaging, it is convenient to perform studies earlier and with a smaller patient sample size, which aids in identifying patient populations who might respond the best and benefit the most from treatment.²⁸ Therefore, it would be prudent to implement PET imaging strategies more frequently during the early phases of drug development. The various applications of PET imaging in drug discovery are illustrated in Fig. 1. In this review, we mainly discuss the utilization of PET imaging in drug discovery based on the assessable PK and pharmacodynamics parameters. Although we focus on PET imaging in the discovery of drugs for CNS diseases, we also introduce its usage in oncological and cardiac diseases.