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August 2001
Vol. 4, No. 7, pp 59–60, 62.
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Imaging for pharmacology:
A PET project
Positron emission tomography enhances drug development.

Thinking about PET
Thinking about PET. The medical imaging system can quickly tell if there is something on your mind (brain).
The atmosphere at the pharmaceutical company R&D meeting was tense. Past and future budgetary concerns, coupled with problems obtaining toxicity, dose–response, and efficacy data for their newest antidepressant drug, were to blame. Questions abounded. Would the drug reach its target brain sites in humans? What maximum concentrations could be reached? Would a derivative have a longer physiological half-life? A greater margin of safety? When would they know? With 20/20 hindsight, the team lamented the absence of positron emission tomography (PET) imaging data in its drug development strategy.

PET imaging
PET has the unique ability to provide a dynamic view of physiological functions, in contrast to other imaging modalities, which are limited to generating static anatomical pictures. PET delivers virtually “real-time” data that can quantify drug distribution, kinetics, and likely mode of action on selected body functions (e.g., metabolism and blood flow).

A drug, or a biomolecule that serves as a marker for some physiological function, is labeled with an isotope that emits positrons—subatomic particles akin to positively charged electrons. Commonly used isotopes include 11C, 13N, 15O, and 18F, which often replaces 1H. Upon administration, typically intravenous (iv), emitted positrons interact internally with electrons, which results in an annihilation event that simultaneously liberates two gamma rays at 180° to each other. This energy is detected externally via photomultipliers in the PET machine encircling the subject, and from this information, its approximate origin within the body is extrapolated. Approximately 500,000 annihilation events constitute a slice or scan of body tissues.

Scans allow visualization of the internal locations of the marker (e.g., 11C-glucose as a measure of glucose metabolism), and the intensity of the radiation is proportional to the concentration of labeled compound. Anatomical considerations and correlation of the range of radiation densities (in counts per second per milliliter of tissue) with colors of the spectrum provide color representations of a drug or a physiological function in organs and subregions. Typical resolution in humans is 4–7 mm.

PET tracers
Of course, successfully using PET imaging in any study requires consideration of the innate properties of both radioisotope and tracer molecules. 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 to 110 min (11C and 18F, respectively); all steps from cyclotron generation to subject administration must occur within the useful lifespan of the label—approximately three half-lives—to maximize the signal-to-noise ratio.

Ideally, PET tracer molecules should have properties that accurately reflect what they are meant to measure. Such measures include high target site selectivity, a high specific/nonspecific binding ratio, high sensitivity, minimal metabolism, and attainment of equilibrium within the study duration. Carefully considered, PET tracers can be successfully used to address pharmacodynamic and pharmacokinetic issues in drug research, development, and therapy.

PET imaging noninvasively determines the nature of a drug’s interactions with a living organism, including its distribution pattern, general mode of action, and impact on functional end points primarily related to physiological processes. The processes that PET can quantify include glycolysis, protein synthesis, oxygen utilization, cell proliferation, oxidative metabolism, dopamine metabolism, and tissue perfusion (blood flow). Studying these processes helps to diagnose diseases, track disease progression, and assess subsequent drug therapies. The predominant medical conditions and treatments that have used PET include cancer and disorders of the heart and brain.

Studying the effects of a drug on a biological process entails using the appropriate biomolecular marker as the tracer and not the drug itself. For example, the success of a cancer chemotherapeutic is evaluated on the basis of its ability to decrease tumor metabolism (and hence, growth), which is assessed by a drop in glucose uptake by tumor cells. Glucose is in high demand as an energy source for rapidly dividing tumor cells. A 11C- or 18F-labeled 2-deoxyglucose tracer (a nonmetabolized glucose analogue) can first be used to establish a baseline tumor growth rate (the glucose utilization rate) in a patient and then to assess antitumor activity after a drug regimen. Radiolabeled amino acids are used similarly to monitor decreases in tumor protein synthesis that correlate with drug efficacy.

PET also can measure drug effects on region-specific brain functions. For a given drug, the capacity and occupancy of brain receptor molecules (the sites of action of antipsychotic drugs) and transporter molecules (associated with drug addiction and drugs of intervention) can be assessed. Tracers that bind to these molecules generate regional maps of receptors and transporters, estimate receptor and transporter occupancy by drugs of interest, and correlate degrees of clinical efficacy. The short half-lives of PET isotopes also make before-and-after study design feasible for a single subject on the same day.

Along with pharmacodynamics, PET can provide critical information about what happens to a drug over time (its pharmacokinetics)—which is essential to efficacious and cost-effective drug development. Obtaining pharmacokinetic data with PET usually involves injection or inhalation of the labeled drug followed by repeated PET measurements in organs or subregions (so-called regions of interest) over a specified time course. These data are used to generate time–activity curves of the extent of radiation (drug) uptake over time. When used in conjunction with similarly timed measurements of plasma drug concentrations and an appropriate model of the major body compartments into which the drug is distributed, estimates for many standard pharmacokinetic parameters can be derived. Possible parameters include the timing and scale of peak dose, “area under the curve” estimates of total drug concentrations, bioavailability, biological half-life, uptake and elimination rate constants, and organ clearance.

For receptor-mediated drugs, kinetic measurements encompass maximal receptor binding capacity, receptor affinity (measured by the dissociation constant), the time course of receptor binding and clearance, and interactions with competitors. This application of PET has seen great use for drugs that interact with the central nervous system (CNS) and mediate nerve signal transmission.

Receptor occupancy studies using PET have been performed for numerous CNS receptors and have implications for various CNS-related conditions. In schizophrenic patients treated with the antipsychotic drug raclopride, PET was used to visualize occupancy of a specific brain dopamine receptor correlated with antipsychotic effects. However, the receptor occupancy fraction was the same for responders and nonresponders, suggesting that variability in the response to the drug is not a product of binding alone. Also, receptor occupation occurred much faster (hours) than the manifestation of antipsychotic effects (days or weeks), supporting the idea that drug binding is a prerequisite in a series of more complex, long-term events.

Monoamine transporters (MATs) mediate the uptake of chemical messengers involved in nerve transmission. If MATs are blocked, neurotransmitters remain indefinitely at the nerve terminal and nerve signals can propagate endlessly.

Cocaine exerts its stimulatory and addictive effects through blockage of the dopamine MAT. PET has shown that methyl phenidate (Ritalin), prescribed for attention deficit–hyperactivity disorder in children, also blocks the dopamine MAT. Ritalin increases brain dopamine within 60 min of ingestion yet does not lead to abuse or a “high” the way cocaine does, even with a >70% MAT occupancy. Differences in routes of uptake and distribution of the two drugs (Ritalin is given orally, while cocaine is typically inhaled) and extents of MAT occupation appear to be responsible. Route-dependent effects can greatly influence pharmacodynamics and pharmacokinetics.

Tracer administration
Although oral medications abound, PET studies preferentially use the iv route. Its rapid delivery, systemic distribution, and bypass of gastrointestinal metabolism make it ideal. This is not the case, however, for oral administration. In light of its preformulation needs, slow absorption, and systemic distribution, and given the short isotopic half-lives of PET tracers, the oral route is less attractive. Indeed, in a recent PET study of receptor binding that compared oral and iv routes, compounds taken orally showed significantly lower specific binding, higher nonspecific binding, and decreased ability to produce useful PET scans.

Inhalation is the second most prevalent route for PET imaging, primarily for direct-acting drugs targeted to the lungs, such as antiasthmatics. Complications associated with this route, although less substantive than for the oral route, involve throat problems, technical challenges with the dispersal device, physicochemical interactions between drug and vehicle, and patient-related usage issues. Reproducible dose delivery and pharmacokinetic parameters, however, can still be established.

A bright future
The development of the MicroPET, an imaging system that offers 2-mm resolution and is tailored to laboratory rodents, promises advantages for preclinical screening of drugs for functional, distributional, and kinetic properties. Another recent development is fusion imaging, which allows direct overlay of anatomical features onto PET images using back-to-back computerized tomography and PET in a single scan, such that accurate regional quantitation can be greatly enhanced. Such advances will increase the efficiency of PET as a screening method for the anticipated wealth of new molecular targets and active substances emerging from genomics, proteomics, and combinatorial chemistry.

PET’s rapid, noninvasive visualization of dynamic interactions between drugs and biological systems ensures it an ever-growing role in the future of pharmaceuticals.

Further reading

  • Fischman, A. J.; Bonab, A. A.; Rubin, R. H. Regional pharmacokinetics of orally administered PET tracers. Curr. Pharm. Design 2000, 6, 1625–1629.
  • The University of California at Los Angeles’s Crump Institute for Molecular Imaging offers a tutorial called “Let’s Play PET” (available at www.crump.ucla.edu/lpp/lpphome.html).
  • van Waarde, A. Measuring receptor occupancy with PET. Curr. Pharm. Design 2000, 6, 1593–1610.

Elizabeth McKenna is a toxicology and health sciences consultant and freelance writer living in White Hall, MD. Send your comments or questions regarding this article to mdd@acs.org or the Editorial Office by fax at 202-776-8166 or by post at 1155 16th Street, NW; Washington, DC 20036.

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