Quantification of D₂-like dopamine receptors in the human brain with ¹⁸F-desmethoxyfallypride

Substituted benzamides such as ¹¹C-raclopride or ¹²³I-iodobenzamide are selective radiotracers for PET and SPECT imaging of D₂-like dopamine (DA) receptors. ¹⁸F-Desmethoxyfallypride (18F-DMFP) is a benzamide tracer with the advantage of an ¹⁸F label. We optimized the synthesis and evaluated ¹⁸F-DMFP in PET studies on healthy human volunteers. Methods: The affinity of DMFP for D₂-like DA receptors was characterized in vitro using membrane preparations from rat striatum and the DA receptor ligand ³H-spiperone. PET studies on 10 healthy human volunteers were performed using a whole-body PET scanner after injection of 214 ± 54 MBq (mean ± SD) ¹⁸F-DMFP. Brain images were acquired dynamically over 124 min, and metabolite-corrected plasma activity was used as the input function. Data analysis was performed using several different approaches (compartmental, graphical, equilibrium methods). Results: The mean inhibition constant (K_i) of DMFP was 15 ± 9 nmol/L. In human brain, the striatum-to-cerebellum ratio reached a maximum of about 4 between 60 and 120 min. When specific binding in the striatum was expressed as the difference between binding in the striatum and the cerebellum, it reached a maximum at approximately 60 min after injection and remained almost constant until the end of data acquisition. The ratio of specific striatal to nonspecific cerebellar binding was about 3:1 at 120 min after injection. A small, but significant specific tracer binding could also be detected in the thalamus. Treatment of a schizophrenic patient with a high dose (1,000 mg/d) of another substituted benzamide, amisulpride, resulted in a reduction of specific tracer uptake of about 90% in striatal regions. With regard to measured distribution volumes and binding potentials, there was an excellent agreement between all applied analytic methods. Conclusion: Our study demonstrates that ¹⁸F-DMFP is a highly reliable tracer for PET imaging of D₂-like DA receptors. It offers the major advantage that it can be used independently of an on-site cyclotron within a PET satellite network. Noninvasive analytic methods without blood sampling provide valid measurements of receptor quantities in human striatum. Because of the ¹⁸F label and the favorable imaging properties, ¹⁸F-DMFP could become an efficient substitute for ¹¹C-raclopride in a clinical context.