[18F]Fallypride is a new and promising radiotracer, suitable for imaging D2 receptors with Positron Emission Tomography (PET) in both striatal and extrastriatal regions. The high signal to noise ratio of [18F]fallypride has been attributed to its high affinity for D2 receptors (K D of 0.03 nM, measured in vitro at room temperature).
We sought to further characterize this tracer in terms of its in vivo affinity, possible affinity differences between brain regions and dependence of in vitro affinity on temperature.
PET scans were performed in baboons over a wide range of concentrations to measure the in vivo K D of [18F]fallypride in striatal and extrastriatal regions. Several analytical approaches were used, including nonlinear kinetic modeling and equilibrium methods. Also, in vitro assays were performed at 22 and 37°C.
No significant differences in the in vivo K D were detected between regions. In vivo K D of [18F]fallypride was 0.22±0.05 nM in striatum, 0.17±0.05 nM in thalamus, and 0.21±0.07 nM in hippocampus. These values were intermediate between in vitro K D measured at 22 (0.04±0.03 nM) and 37 degrees (2.03±1.07 nM).
The in vivo affinity of [18F]fallypride was not as high as previously estimated from in vitro values. This property might contribute to the favorable kinetic properties of the tracer. The in vivo affinity was similar between striatal and extrastriatal regions. This result indicates that the measured regional in vivo affinities of this tracer are not affected by putative regional differences in endogenous dopamine, and that [18F]fallypride is an appropriate tool to provide unbiased estimates of the occupancy of D2 receptors by antipsychotic drugs in striatal and extrastriatal regions.
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The authors would like to thank Samir Abdelhadi, Mohammed Ali, Elizabeth Hackett, Kimchung Ngo, Van Phan, and Lyudmilla Savenkova for excellent technical assistance. Supported by the National Alliance for Research in Schizophrenia and Depression (NARSAD), the Lieber Center for Schizophrenia Research at Columbia University and the Public Health Service (NIMH K02 MH01603-0, NIMH MH59342-01, NIAAA IP50 AA-1287001).
Simulations were performed to test the combined effects of three error sources on K D estimation using the TAC method, where ROI–CER is used as an estimate of bound concentration: (1) differences in kinetics between CER and C 2, (2) failure to accurately capture the peak specific binding due to discrete sampling and (3) differences in nonspecific binding between CER and ROIs. Simulated CER and ROI were constructed according to Eq. 2 and the system given by Eqs. 15, 16, respectively. All parameters were obtained from the experimental data as the average over the tracer dose experiments. Plasma curves were formed as a line segment from 0 to peak value during time t=0 to 1.5 min and a sum of three decaying exponentials from t=1.5 to 200 min. Kinetic parameters for CER and ROI were [K′1, k′2]=[0.37, 0.19] and [K 1, k 2, k 3, k 4, k +]=[0.56, 0.56/V 2, B max×k +, 0.03, 0.03×f 2/K D], respectively. K D was fixed at 0.2 nM; f 2 was computed as f 1×V 2 with f 1 fixed at 0.28. Three levels of nonspecific binding differences were used. V 2 was set to 0.9, 1 and 1.1 times K′1/k′2, corresponding to the range seen in the blocking experiments. At each level of V 2, B max ranged from 2.5 to 24 nM. For each B max and V 2 pair, six curves were formed with plasma magnitudes in proportion to the six injected masses from the real data. Simulated PET data were then formed by sampling these curves at the midframe times of the PET protocol. Scatchard plots were formed using ROI–CER to estimate peak bound and CER to estimate free plus nonspecifically bound concentration at the time of peak bound. The results are shown in Fig. 6. Estimated K D is plotted against B max for each level of V 2, yielding three curves. For B max≤5, K D is overestimated at all levels of V 2, with the overestimation higher at V 2=1.1 × CER distribution volume (similar to V 2 of hippocampus in blocking studies) than at V 2=0.9 × CER distribution volume (similar to V 2 of thalamus in blocking studies). For B max≥20 nM (similar to striatum), K D estimates are close to true K D at all levels of V 2.
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Slifstein, M., Hwang, DR., Huang, Y. et al. In vivo affinity of [18F]fallypride for striatal and extrastriatal dopamine D2 receptors in nonhuman primates. Psychopharmacology 175, 274–286 (2004). https://doi.org/10.1007/s00213-004-1830-x
- Positron emission tomography
- D2 receptor imaging