Radiosynthesis and biodistribution of the S-[ 18F]fluoroethyl analog of McN5652

[ 11C]McN5652 has been reported to exhibit favorable properties as a PET radiotracer for studying serotonin uptake sites. However, the use of this radiotracer may be limited by the short half-life of 11C. To obtain a tracer with longer physical half-life, we have synthesized the S-[ 18F]fluoroethyl analog of McN5652 (trans-1,2,3,5,6,10b-hexahydro-6-[4-([ 18F]fluoroethylthio)-phenyl]pyrrolo-[2,1-a]-isoquinoline) ([ 18F]FEMcN) and evaluated as a PET radiotracer for imaging serotonin uptake sites. The radiosynthesis was performed via a one-pot, two-step procedure. In the first step, 1-bromo-2-[ 18F]fluoroethane was prepared from 2-bromoethyl triflate and K 18F/Kryptofix 2.2.2. in THF at room temperature. The second step, the S-fluoroalkylation of the normethyl McN5652, a thiol, was carried out, without isolating the 1-bromo-2[ 18F] fluoroethane, by adding the normethyl McN5652 to the reaction vial, which was warmed at 45 °C for 1 min. The fluoroalkylation reaction proceeded quickly, giving [ 18F]FEMcN in an average overall radiochemical yield of 13 ± 7%. The specific activity was 1593 ± 625 mCi/μmol. Ex vivo autoradiographic studies revealed that [ 18F]FEMcN accumulated into regions with high densities of 5-HT uptake sites such as hypothalamus, substantia nigra, and raphe nuclei. With blockade by nitroquipazine, a selective and highly potent 5-HT uptake blocker, the activity level in these regions was close to that in regions low in 5-HT uptake sites such as cerebellum, suggesting that this radiotracer binds specifically to 5-HT uptake sites. The regional distribution of [ 18F]FEMcN at 60 min postinjection correlated with the distribution of [ 11C]McN5652 reported in the literature. The specific binding of this radiotracer determined as the difference in radioactivity accumulation with and without blocking by the 5-HT uptake blocker agreed with the distribution of the number of 5-HT uptake sites measured in vitro. Thus, 5-HT uptake sites were visualized in vivo with [ 18F]FEMcN. However, comparison with the in vivo behavior of [ 11C]McN5652 indicated less favorable properties of [ 18F]FEMcN as a PET radiotracer for imaging 5-HT uptake sites, including lower blood-brain barrier penetration and lower target-to-nontarget ratios.