18F-Norfallypride: A new PET radiotracer for imaging dopamine D3 receptors

Objectives Dopamine D3 receptors are involved in cognition, memory, reward and other brain functions. We have developed ¹⁸F-Norfallypride ((S)-N-[(2-pyrolidinyl)methyl]-2,3-dimethoxy-5-(3’-flouropropyl)benzamide) and evaluated its use as a potential PET imaging agent.

Methods Norfallypride was synthesized using (S)-1-BOC-2-(aminomethyl)pyrrolidine with modified procedures (Mukherjee et al., 1995). Tosylate ((S)-N-[(1-BOC-2-pyrolidinyl)methyl]-2,3-dimethoxy-5-(3’-tosyloxypropyl)benzamide) was radiolabeled with ¹⁸F-Kryptofix-K₂CO₃ in CH₃CN at 96°C for 30 min and deprotected with TFA at 80°C to yield ¹⁸F-Norfallypride. In vitro binding on 10 μm brain slices were carried out. MicroPET imaging in rats (after 0.8-1 mCi iv) was carried out followed by autoradiographic analysis on 40 μm brain slices.

Results ¹⁸F-Norfallypride was made in modest yields in specific activities of >2Ci/μmol (60%CH₃CN-0.1%Et₃N in water, flow rate 2.5 ml/min-C18 semiprep; ret. time 21 min). Compared to fallypride, affinity of norfallypride for dopamine D2 receptors was reduced to 0.63 μM. In vitro studies indicated selective binding to the striata (ST) (ratio of 4 ST/Cerebellum (Cb)) which was displaced by 10μm sulpiride. Low brain uptake of ¹⁸F-Norfallypride was seen in the rat. Ex vivo scan of the brain revealed binding to several regions and ex vivo micropet autoradiographic analyses gave ratios with respect to Cb: ST=9.8; Nucleus accumbens(NA)=5.8; Hippocampus(HP)=5.9; Hypothalamus(HT)=9.3; Cerebellar Nuclei(CN)=6.7.

Conclusions ¹⁸F-Norfallypride binds uniquely to brain regions known to contain D3 receptors. Observed binding to the HP has hitherto not been reported.

Research Support NIH R01 EB006110