Positron Emitter Labeled Enzyme Inhibitors and Substrates

Of the new medical imaging modalities, Positron Emission Tomography (PET) is uniquely capable of examining biochemical transformations and measuring drug pharmacokinetics in the living human and animal body (1). In essence, the PET method involves administering a positron emitter labeled radiotracer and measuring the accumulation of labeled product. The positron 268emitted from a decaying isotope annihilates by interacting with an electron producing two body-penetrating photons which are emitted at an approximately 180 degree angle to each other. The detector (the positron emission tomograph) uses coincidence detection to locate the source of the annihilation photons within the object and to measure the concentration of the labeled compound. This is a technique which can be safely applied in humans because the commonly used isotopes have a short half life and decay to non-radioactive daughter products (Table 1). In addition, the specific activity of radiotracers labeled with the positron emitters is exceedingly high allowing their use as true tracers even for such pharmacologically sensitive measurements as receptor-radioligand interactions. Although the translation of the radioactivity concentration in tissue as measured by PET (and the radioactivity concentration in plasma, or in some reference tissue) to meaningful biochemical parameters (ie rate of glucose metabolism, concentration of neurotransmitter receptor, tissue pH, etc.) requires the application of a tracer kinetic model, it is important to emphasize that it is the design of highly selective radiotracers, the biochemical characterization of the uptake process, and the identification of the rate limiting reactions which are the foundation of the PET method. Table 1 Physical Properties of ¹¹C, ¹⁵O, ¹³N and ¹⁸F

NUCLIDE

HALF-LIFE

DECAY MODE

DECAY PRODUCT

MAXIMUM SPECIFIC ACTIVITY (Ci/mol)

11_C

20.4 min

β⁺(99+%)

11_B

9.22 × 10⁹

15_O

2.07 min

β⁺(99.9%)

15_N

9.08 × 10¹⁰

¹³N

9.96 min

β⁺(100%)

13_C

1.89 × 10¹⁰

18_F

109.7 min

β⁺ (97%)

18_O

1.71 × 10⁹