Nuclear medicine in general and PET imaging in particular have long provided the opportunity for quantitative measurements of human physiology in vivo. Practical methodology for these measurements came to pass in the late 1970s and early 1980s as PET scanners provided quantitative images of radioactivity in humans after injection of radiopharmaceuticals. Furthermore, studies on the human brain became a focus because image quality for the brain was far superior to that for other parts of the body, for reasons such as the lower attenuation in the head. An obvious target for quantification was cerebral blood flow (CBF), using the elegantly simple flow agent 15O-water. After intravenous injection, water arrives rapidly in the brain and is extracted with high efficiency, so that the initial uptake is nearly proportional to blood flow.

In the 1980s, several groups were working on methods for quantification of blood flow with 15O-water. The Washington University group developed elegant quantification methods, presented in seminal papers by Herscovitch et al. and Raichle et al. in 1983 (1, 2). The methodology was challenging, involving producing an isotope with a 2-min half-life, rapidly producing labeled water in injectable form, delivering a bolus injection with more than 925 MBq (25 mCi) of activity, rapidly collecting arterial samples to define the blood time–activity curve, and, of course, acquiring and reconstructing PET images. These were not experiments to be undertaken by the faint of heart. The 1983 papers of Herscovitch, Raichle, and their colleagues exemplified the ideal approach for development of quantitative imaging assays with PET. First, the authors based their studies on classic tracer methods and kinetic modeling techniques, in which they used equations to explain the relationship between the tissue radioactivity data and the underlying physiologic parameter of interest, that is, CBF. They used nonhuman primate studies to validate the PET measures against established, nontomographic flow approaches. Further, they found ways to simplify the approach