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 of11C. 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 K18F/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 degrees C for 1 min. The fluoroalkylation reaction proceeded quickly, giving [18F]FEMcN in an average overall radio-chemical yield of 13 +/- 7%. The specific activity was 1593 +/- 625 mCi/mumol. 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.
Suehiro
M
M
Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104-6063, USA.
Greenberg
J H
JH
Shiue
C Y
CY
Gonzalez
C
C
Dembowski
B
B
Reivich
M
M
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000493:pharmacokinetics; D007553:Isotope Labeling / Q000379:methods; D051379:Mice; D011758:Pyrroles / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
C102680:1,2,3,5,6,10b-hexahydro-6-(4-(fluoroethylthio)phenyl)pyrrolo(2,1-a)isoquinoline; D005462:Fluorine Radioisotopes; D006845:Hydrocarbons, Fluorinated; D011758:Pyrroles; D011804:Quinolines