Positron Emission Tomography in Drug Development

Positron emission tomography (PET) is widely recognized as the paradigm of molecular imaging. Its strengths as an imaging method include high photon detection efficiency and spatial resolution by comparison with conventional radionuclide imaging (e.g., SPECT), high quantitative accuracy, and a wide variety of radiopharmaceuticals that can be used to interrogate regional physiology or pathophysiology. Over the last decade, positron emission tomography (PET) has emerged from its previously limited role as a research tool into a widely used clinical method, most notably for imaging of cancer and various neurologic disorders. The recent advent and rapid dissemination worldwide of integrated PET/CT scanners has increased the power of this imaging technique by allowing for simultaneous acquisition of functional and anatomical images.

PET / CT in Drug Development

PET and PET/CT have become increasingly important tools in the process of drug development, especially for novel anticancer drugs. Assessment of tumor metabolism with the glucose analogue 18F-fluorodeoxyglucose (FDG) FDG is the most widely used PET imaging method in oncology, exploiting the fact that most malignant tumors exhibit an increased rate of glucose utilization. At the simplest level, the improved accuracy of cancer staging provided by FDG-PET is now used routinely in many clinical trials to ensure that patients are properly staged before registration; this is especially important in trials of neoadjuvant therapy for locally advanced disease (to exclude subjectswith otherwise occult distant metastatic disease). A more relevant use of FDGPETin the early clinical phases of drug development is as a biomarker of response to therapy.Studies in many different types of cancer, treated with a variety of cytotoxic and cytostatic therapies, have shown that tumor FDG uptake typically decreases with effective therapy.

More importantly, this decrease in tumor glucose metabolism nearly always occurs sooner than does a change in tumor volume assessed by anatomical imaging and typically occurs with cytostatic agents despite no change in tumor volume (e.g., imatinib mesylate for treatment of gastrointestinal stromal tumor). Accordingly, by incorporation of FDG-PET into a phase I trial, identification of drug activity across a spectrum of advanced tumors can be accomplished in addition to determination of the maximum tolerated dose. Similarly, FDG-PET can be used for earlier stopping of phase II trials where little or no activity is demonstrated. Ultimately, where only a subset of patients respond to a particular therapy, an early documentation of non-response by FDG-PET may be the basis for determining that the treatmentshould be discontinued in favor of an alternative regimen.A similar approach to early response assessment, usinganalogs of thymidine such as 3’-deoxy-3’-18F-fluorothymidine(FLT), tracks the rate of DNA synthesis in the tumor, and maybe an even better biomarker with some therapies.

The generic information provided by imaging with FDG or FLT will often not be sufficient to address other important questions in early drug development, such as whether the target of interest is present in the tumor of a trial candidate, whether the drug is reaching its target, or whether it is inhibiting the activity of the target at achievable drug concentrations. The ability to incorporate the positron-emitting radionuclides carbon-11 and fluorine-18 into many small-molecule drugs without altering their behavior, and at pico- or nanomolar levels of the tracer, makes PET a uniquely powerful way to answer such questions. Serial imaging is a more practical and more readily accepted means to study the “target” than is serial tissue sampling.

As just one such example, PET with 18F-fluoroestradiol, a radiolabeled estrogen, can be used to identify which women with estrogen-receptor-positive breast cancers are likely to respond to hormonal therapy and to study whether therapies designed to alter estrogen-receptor expression or function are working in vivo. Polypeptide or protein drugs, such as somatostatin analogs and anti-tumor monoclonal antibodies, can be labeled with various positron emitters (e.g., 64Cu, 68Ga), so that PET can be used to study drug biodistribution and pharmacokinetics, as well as binding and binding affinity to target receptors or antigens in the tumor, and the relationship of binding to response.

Positron Emission Tomography

Other important aspects of tumor biology that are relevant to understanding the mechanisms of drug action can be evaluated by PET and embedded as correlative studies in early-phase clinical trials. Examples include quantification of tumor blood flow (as marker of angiogenesis), hypoxia (as one marker of resistance to therapy), and apoptosis; PET tracers for studying all of these processes are available.

PET also has importance in drug development in fields other than oncology. Notable examples in neurology include receptor occupancy and pharmacokinetic studies of various neuroreceptor ligands and the increasing use of amyloidbinding Positron Emission Tomography tracers to assess the effectiveness of novel treatments for Alzheimer’s disease.

“Over the last decade, PET has emerged from its previously limited role as a research tool into a widely used clinical method, most notably for imaging of cancer and various neurologic disorders.”