Medicines crystal ball
Positron emission tomography (PET) provides many lifesaving answers.
In the hallway outside the PET Imaging Center, the man sat drumming his fingers nervously, waiting his turn. After two weeks of chemotherapy, he needed to know how effectively the drugs were reducing the tumor in his lung and whether his cancer was still spreading. Beside him sat an older woman, there to discover if her memory loss might be due to the onset of Alzheimers disease. Across from her was a younger woman, impatient to learn whether her recurring chest pains were signs of heart disease. Amazingly, by assessing select body functions and without surgical procedures, PET would deliver their answers.
Used most commonly in the diagnosis, monitoring, and therapeutic targeting of health ailments such as cancers, cardiovascular disease, and brain disorders, PET provides an intimate look into how the body functions at physiological and biochemical levels. For a disease like cancer, it surpasses answering simpler imaging questions, such as Where is it? and What could it be?, by addressing complex questions like Is it malignant?, Has it spread, and to where?, Does the therapy need to be altered?, and Is it back again?. Moreover, PET provides answers at earlier stages of diseases, a factor that can be lifesaving.
Understanding the quantum leap that PET has provided to biomedical imaging requires journeying within both the atom and the living organism. An integration of nuclear physics, radiochemistry, synthetic organic chemistry, human physiology, pharmacokinetics, and computer programming, PET provides a crystal ball view of our health and welfare.
The seemingly impossible knowledge provided by PETthe noninvasive, real-time insight into cellular metabolism and molecular functionis limited only by our capacity to develop and synthesize safe and effective radioactive molecules or tracers that serve as internal markers.
Conceptually, PET requires a radiolabeled molecule, a means of measuring emitted radiation after the molecule is internalized, and algorithms to convert patterns of captured signals into two-dimensional cross sections or slices through a body. Three-dimensionality requires additional reconstructive tinkering, along with longer processing times and extensive computational power. Practically, PET translates into a substantial investment, primarily in a small cyclotron (to prepare radioisotopes), a collection of molecular synthetic apparatuses, and a tomographotherwise, close proximity to a PET facility is essential. The key to the process is the ability to transform common atoms found in drugs or biological molecules into radioactive, positron-emitting isotopes.
A biomolecule that serves as a marker for some function can be labeled with an isotope that emits positronssubatomic particles akin to positively charged electronssuch as 11C, 13N, and 15O, as well as 18F, which often replaces 1H. Upon tracer administration, emitted positrons interact with electrons from atoms in nearby tissues, usually within 1 mm. The collisions result in annihilation events that each simultaneously liberate two gamma rays at 180°. A scintillator (bismuth germanate is standard) and photomultipliers in the tomograph encircling the subject detect this energy pattern and extrapolate the approximate origin of the energy. About 500,000 annihilation events constitute a single slice or scan of body tissues.
Scans allow visualization of the internal locations of the tracers, designed for measuring general body functions (e.g., glucose metabolism or blood flow in an organ) or highly specific functions (e.g., occupancy of a subtype of brain dopamine receptor). The intensity of emitted gamma radiation is proportional to the tracer concentration. Anatomical considerations and correlation of the range of radiation densities with colors of the spectrum provide quantitative and/or color representations of the magnitude of a physiological function. In humans, typical tissue resolution with PET is 47 mmthe width of a pencil.
The potential for development of a PET system was realized in the 1950s, when interest in positron-emitting isotopes emerged. Invention of the PET scanner in the early 1970s is credited to Michael E. Phelps. A co-founder of CTI, Inc., a leader in PET products and services, he received the Enrico Fermi Award for his invention. By the 1980s, the vision had become a reality, and PET was being used routinely for medical diagnosis and studies of human metabolism and brain activation (see How Does PET Compare).
PET tracers can be divided into three broad categories based on what they measure.
- The first type of tracer provides general metabolic data, such as glucose uptake and protein synthesis, via labeled biomolecules (e.g., 11C-deoxyglucose and 11C-methionine, respectively) that leave the bloodstream and enter cells.
- The second type provides estimates for grosser physiological parameters, such as blood flow (e.g., 15OH2O or 11CO2), and essentially remains in the bloodstream over the effective study duration.
- The third tracer type delineates and quantifies highly specific molecular targets, such as cellular receptors and transporters, for which tracers are either endogenous ligands or drugs (e.g., 11C-raclopride for the DA2 dopamine receptor).
The high specific activity and sensitivity of PET tracers make them well suited for studying molecular targets present to low nanomolar concentrations.
The design or selection of the optimal PET tracer is an exercise in integrating knowledge of cellular physiology and biochemistry, advances in radio- and synthetic chemistry, tracer pharmacology and kinetics, and refinements in cyclotron and PET technologies. Of course, successful PET imaging requires consideration of the innate properties of both radioisotope and tracer molecule, and the route of tracer administration.
Radioisotope selection criteria must include the ability to incorporate the isotope into the molecule of interest and the appropriateness of its radioactive half-life for the study design. Half-lives of positron emitters range from 20 min (11C) to 110 min (18F). All steps, from cyclotron generation to subject administration, must occur within the useful lifespan of the labelapproximately 3 half-livesto maximize the signal-to-noise ratio.
Ideally, PET tracers have properties that accurately reflect what they are meant to measure and minimize radiolabeling effects on the parent molecule. Such properties include high target-site selectivity, specificity, sensitivity, minimal metabolism, and the attainment of equilibrium in the body during the study. All aspects require prior validation.
Inherent in tracer design is consideration of the tracer administration route. Intravenous tracers, by virtue of their rapid delivery, systemic distribution, and bypassing of gastrointestinal metabolism, are ideal and are most common. Inhalation, the second most prevalent administration route, suffers from complications related to swallowing, dispersal, physicochemical interactions between drug and vehicle, and patient-related issues. Ingested tracers are characterized by slower absorption, systemic distribution, and a greater chance of metabolites forming, making them much less attractive.
Biomedical Uses of PET
PET assists greatly with diagnosis, treatment, and follow-up of cancers, cardiovascular diseases, and disorders and addictions of the brain and central nervous system. Thus, PET tracers are tailored to measure varying diagnostic end points, treatments, and therapeutic outcomes.
Cancer. Early diagnosis and treatment of cancer are often crucial to a good prognosis. PET allows the detection of cancerous cells before tumors even form and can sometimes obviate the need for biopsies. PETs ability to detect tumors, determine malignancy and cancer progression, and ascertain cancer metastases stems from its capacity to assess the relatively higher energy needs of actively growing cancer cells.
Glucose is in higher demand as an energy source by rapidly dividing cancer cells than by normal cells. Using a 11C- or 18F-labeled 2-deoxyglucose tracer (a nonmetabolized glucose analogue), PET can detect cancer and establish a baseline tumor growth rate (the glucose utilization rate) in a patient. It can also assess antitumor activity during and after therapy. Successful therapy depends on eliminating tumor growth (metabolism), which is determined by decreased glucose uptake by tumor cells. Radiolabeled amino acids can be used in a similar way to deoxyglucose. Other indices of tumor growth, such as the extent and rate of tumor perfusion, and their projected decreases with treatment, can also be determined.
Cardiovascular Disease. PET has proved extremely useful in the study and quantification of various aspects of heart and blood vessel function. As with cancer, clinical studies show an important role for PET in diagnosing patients, describing disease, and developing treatment strategies. PET has been applied in two major areas: assessment of coronary artery disease and impaired blood flow, and determination of the viability of heart tissue for revascularization. The latter helps physicians decide whether bypass surgery or heart transplant is a more viable option for a patient.
Tracers that assess blood flow (e.g., 15OH2O, 11CO2, and 13NH3) help establish the extent and progression of arterial blockage as well as the efficacy of drug therapy or surgery. They also are used to monitor the recovery and maintenance of a blockage-free state.
Central Nervous System Conditions. PET can be used to diagnose functional brain disorders, such as Alzheimers and Parkinsons diseases, childhood seizures, brain development disorders, and brain tumors. Cause and effect can also be investigated. In memory loss, PET can ascertain whether the loss is due to decreased blood flow, depression, or a molecular depletion, as in Alzheimers disease. In addition, the appropriateness of therapies or interventions for these disorders can be monitored. PET even maps brain regions involved in specific activities, such as laughing, hearing, memory, and emotions, a useful function for planning neurosurgical procedures.
PET also can measure the effects of drugs on region-specific brain functions. For a given drug, the capacity and occupancy of brain receptor moleculesthe sites of action of antipsychotic drugsand transporter moleculesassociated with drug addiction and drugs of interventioncan be assessed. Tracers that bind to these molecules generate regional maps of receptors and transporters, estimate their occupancy by drugs of interest, and correlate drug occupancy with degrees of clinical efficacy.
Hundreds of specific radiopharmaceuticals can be synthesized for studying brain function, to augment those such as 11C- or 18F-N-methylspiperone for mapping dopamine and serotonin receptors, 11C-flumazenil for benzodiazepine (GABA-associated) receptors, and 11C-carfentanil for opiate receptors.
|PET Radiocompounds and Their Biomedical Applications
||Hypoxic cell tracer
||Dopamine DI receptor
|(Adapted from www.austin.unimelb.edu.au/dept/
The Future of PET
Imaging systems designed for small laboratory animals like rodents, such as the microPET developed at the Crump Institute of Biological Imaging in Los Angeles, offer great research opportunities. Using lutetium orthosilicate as a high-light-yielding scintillator, this miniature PET offers 2-mm resolution, a two- to fourfold enhancement over standard PET. The resolution of the microPET is fast approaching 1 mmthe range of the 11C-generated positron. Enormous potential exists for expanding biomedical research, from imaging gene expression in animal gene therapy trials to noninvasively studying the function, distribution, and kinetics of pharmaceuticals.
Another recent development, fusion imaging, allows the direct overlay of anatomical features onto functional PET images. Fusion imaging uses back-to-back computerized tomography and PET in a single patient scan, thereby eliminating artifacts from patient positioning error seen with the use of two separate machines and greatly enhancing the accuracy of regional quantitation. The cost of the fusion imager, which will be marketed by Siemens CTI PET Systems (Knoxville, TN), is expected to be less than two machines.
These advances will enhance the efficiency of PET as a biomedical tool and promote its ever-growing role in the future of health and biomedicine. Yet the usefulness of PET and the quality of its results will hinge on future abilities to develop and synthesize novel and improved PET tracers that ensure new directions for PET-based research and medicine.
Elizabeth McKenna is a toxicology and health sciences consultant in White Hall, MD. Send your comments or questions regarding this article to email@example.com or the Editorial Office 1155 16th St N.W., Washington, DC 20036.