Concerning Strategies for in vivo Measurement of Receptor Binding Using Positron Emission Tomography

To the Editor: One approach, which has been used for the quantitative analy sis of radioligand neuroreceptor kinetics in the living human brain, is the "ratio" method (Wagner et aI., 1983; Wong et aI., 1984). This approach is based on the observa tion that after injection of the specific D2 dopamine receptor radioligand 3-N-[llC]methy lspiperone (NMSP ) the ratio of radioactivity in the caudatel cerebellum is linear if plotted against a "normalized integral" representing a transformed time coordi nate. In the case of NMSP, the ratio is also linear with respect to time. Validity of the ratio method requires linearity with respect to the normalized in tegral; linearity with respect to time is not required. The ratio method is a useful approach for providing a quantitatiye index of available receptor provided that the process is not diffusion-limited, in which case the kinetic data would primarily reflect radio ligand delivery rather than binding. In a recent critical comparison of the ratio method and an "explicit" method (Perlmutter et aL, 1986), experimental evidence was presented which was taken to demonstrate that the plot of the ratio was nonlinear with respect to the normalized integral. If true in the case of NMSP, this argument would effectively invalidate the ratio method. Be cause the ratio method was proposed for NMSP in humans, but the critical evidence is based on [18F]spiperone in baboons, further work with NMSP in humans would be required for a definitive argument. Another more compelling reason exists which weakens the use of the baboon data as evidence against the ratio method. The low specific activity of the [l8F]spiperone (10-30 Ci/mmol) suggested that the dopamine receptor may be significantly oc cupied in the baboon experiments. Because the ratio method theoretically can be used only when the receptor has insignificant occupancy (that is, a pseudo first-order kinetic situation), a significant occupancy in the baboon experiments would invali date the argument against the ratio method. The requirement for insignificant receptor occu pancy comes about from the implicit definition of