The effect of different compounds in vivo depends on the dose, brain penetration, and target engagement of the compound. Therefore, the best way to compare the effects of compounds is to normalize the concentration of the compounds against the apparent D2 receptor occupancy displacement of specific radiotracers such as 11C-raclopride and 125I-IBZM. Ideally, one would like to quantify the binding of a specific radiotracer before and after neuroleptic treatment to correct for any individual baseline variability of the D2 receptor. Although this is possible with our model, it is usually difficult in the clinical setting; hence, many studies define a binding index (Eq. 1) compared to a normal control population.
where Am and Cerm are the specific radioactive signals in the region of interest, ie, in the striatum and cerebellum, respectively.
We used a radiotracer at a concentration of 1 pM. The Kd of raclopride, IBZM, and FLB457 for the D2 receptor are 1.3 nM, 0.6 nM, and 0.018 nM, respectively.20 (link),21 (link) We defined the apparent D2 receptor occupancy as
where Rdrug and Rcontrol are the receptor tracer occupancies, respectively, in the presence and the absence of the D2 receptor modulator. Because the density of radioactive-sensitive D2 receptor binding sites is about 100-fold lower in the cerebellum than that in the striatum,22 (link) our simulations indicate that applying Eq. 2 results in between 1% and 1.5% error, compared to the correct use of Eq. 1 (data not shown).
Figure 3 shows the effect of different radiotracers on the calculated receptor occupancy for a range of haloperidol doses. The observation that the calculated D2 receptor occupancy level decreases when higher-affinity tracers are used is in line with reported differences between apparent receptor occupancy measured with raclopride and IBZM in the same subjects.23 (link) This can be partially explained by the fact that the greater the affinity a tracer has for a receptor, the more difficult it is for the drug to compete with it and dislodge it.
where Am and Cerm are the specific radioactive signals in the region of interest, ie, in the striatum and cerebellum, respectively.
We used a radiotracer at a concentration of 1 pM. The Kd of raclopride, IBZM, and FLB457 for the D2 receptor are 1.3 nM, 0.6 nM, and 0.018 nM, respectively.20 (link),21 (link) We defined the apparent D2 receptor occupancy as
where Rdrug and Rcontrol are the receptor tracer occupancies, respectively, in the presence and the absence of the D2 receptor modulator. Because the density of radioactive-sensitive D2 receptor binding sites is about 100-fold lower in the cerebellum than that in the striatum,22 (link) our simulations indicate that applying Eq. 2 results in between 1% and 1.5% error, compared to the correct use of Eq. 1 (data not shown).
