Evaluation of a new [18F] labeled tracer targeting synaptic vesicle protein 2C by ex vivo autoradiography and in vivo PET study in rat brain.

Introduction
The synaptic vesicle protein 2 (SV2) family is a group of integral membrane glycoproteins homologous to the major facilitator superfamily and could be involved in several neuronal diseasesa. The binding of the novel, no-carrier-added, [18F] labeled compound [18F]UCB-F to the SV2C isoform was evaluated in rat brain.
Methods
Radiochemistry
No-carrier added [18F]UCB-F was obtained following the method shown in Fig. 1. The identity and purity of the tracer were evaluated by radioUPLC and chiral radioHPLC.
Autoradiography
Sprague Dawley rat brain sections were incubated at RT with buffered [18F]UCB-F solutions and exposed on film. Matching sections were stained with cresyl violet for structural identification.
PET studies
PET studies (Siemens Concorde Focus 120 µPET) were performed under isoflurane anesthesia. The tracer was injected as a bolus via the tail vein. After a 10-min transmission scan to correct for attenuation, dynamic emission data was recorded for a total of 60 min. The impact of P-glycoprotein (P-gp) activity on tracer uptake in the brain was evaluated using cyclosporine (50 mg/kg SC).
Metabolite analysis
During PET studies, arterial blood samples were taken for the measurement of tracer metabolites. Plasma was separated by centrifugation and proteins were acid-precipitated. Metabolites were detected using HPLC and confirmed by gamma counting.
Results
The tracer was obtained with a decay corrected yield of ±10%. Specific activity ranged from 10 GBq/µmol to 40 GBq/µmol.
Ex vivo autoradiography showed that the binding of [18F]UCB-F to SV2C closely matched the expected distribution b (Fig.2).
In vivo PET studies revealed that [18F]UCB-F briefly entered the brain, but exhibited extremely rapid washout. A large accumulation in the liver and intestines was observed.
Metabolite analysis in the plasma revealed high protein binding and rapid metabolism. Inhibition of P-gp transport with cyclosporin had no clear effect on the rapid washout from the brain.
Conclusions
Despite a close match between [18F]UCB-F SV2C binding and the expected brain distribution, the pharmacokinetics in rat brain appear unfavorable for the use of this tracer to quantify SV2C in vivo.
Acknowledgement / References
a Lynch & al (2004) Proc. Natl. Acad. Sci. USA 101:9861
b Janz & Sudhof (1999) Neuroscience 94:1279
c The authors thank the Walloon Region and the FRNS Belgium for financial support.