18F-Festron: A potential serotonin 5-HT3 receptor PET imaging agent

Objectives Ligand-gated ion channels, serotonin 5HT3 receptors are involved in a number of brain functions such as anxiety, neuronal excitation, and emesis. We have developed 18F-Festron (N-[(2-pyrolidinyl)methyl]-2,3-dimethoxy-5-(3’-18F-flouropropyl)benzamide) and used in vitro and in vivo methods to evaluate its potential as a possible PET imaging agent.

Methods In order to synthesize 18F-Festron, Festron Tosylate ((R) or (S)-N-[(1-BOC-2-pyrolidinyl)methyl]-2,3-dimethoxy-5-(3’-tosyloxypropyl)benzamide) was radiolabeled with 18F using Kryptofix and K2CO3 in acetonitrile at 96°C for 30 min and deprotected with trifluoroacetic acid at 80°C to yield (R) or (S)-18F-Festron. In vitro binding was carried out on 10 μm rat brain slices. MicroPET imaging in rats (after 0.5-1 mCi iv) was permormed on an Inveon scanner, and ex vivo autoradiographic studies on 40 μm brain slices were done on the rat brains. Ondansetron was used for nonspecific binding. Various brain regions were ascertained using the Optiquant Image analysis program, ASIPRO and PMOD.

Results 18F-Festron was synthesized in two-steps with modest yields in specific activities of >2Ci/μmol (60%CH3CN-0.1%Et3N in water, flow rate 2.5 ml/min- C18 semiprep). In vitro binding studies indicated weak selective binding to serotonergic regions in the hippocampus, possibly due to the low concentration of 5HT3 receptors. Low brain uptake of 18F-Festron was seen in the rat. Ex vivo MicroPET analysis displayed binding in numerous brain regions consistent with 5HT3 receptor binding. With respect to the cerebellum, ex vivo microPET ratios were: striatum = 3.3; hypothalamus = 2.2; hippocampus = 1.8; area postrema = 2.4 while autoradiographic ratios were 14, 9, 4 and 6 respectively.

Conclusions 18F-Festron exhibited a unique binding profile to rat brain regions known to contain significant amounts of 5HT3 receptors. Efforts are currently underway to increase brain permeability and fully characterize the binding of 18F-Festron to 5HT3 receptors