Imaging of the serotonin transporter with the [¹⁸F]fluoromethyl analogue of (+)-McN5652

Dysfunctions of the serotonin transporter (SERT) may cause numerous psychiatric and neurological diseases. The radiotracer (+)-[¹¹C]McN5652 has the best biological properties for PET investigations of the serotonin transporter state (Suehiro et al., 1993, 53:883-892). Unfortunately, sufficient target-to-nontarget ratios in the human brain were obtained after 115 min (Szabo et al., 1995, 20:37-43), which is out of proportion to the half-life of carbon-11 (20.4 min). Our efforts are therefore directed to develop an ¹⁸F-analogue of (+)-McN5652.
The fluoromethyl analogue of (+)-McN5652 (1) has a similar binding affinity (IC₅₀ 1.5 nM) as ((+)-McN5652. For this reason, we developed a synthesis of the [¹⁸F]fluoromethyl analogue of McN5652 ([¹⁸F]FMe-McN, [¹⁸F]1).
The required fluoromethylation agent [¹⁸F]bromofluoromethane 2 was prepared from[¹⁸F]fluoride and dibromomethane (Eq. 1, decay-corrected radiochemical yield 40%, related to [¹⁸F]F^-). The thioester precursor 3 was hydrolyzed by treatment with TBAH. The resulting thiol 4 was reacted with 2 to yield [¹⁸F]FMe-McN 1 with decay-corrected radiochemical yields of 3-5 % (related to [¹⁸F]F^-) and a specific radioactivity of 1100 - 2400 GBq/µmol.

First autoradiographic ex vivo investigations in rats demonstrated that [¹⁸F]FMe-McN is concentrated in brain regions with a high density of the SERT as raphe nucleus and hypothalamus. After preinjection of the SERT inhibitor fluoxetine, a nonspecific distribution of the radiotracer was observed.
These results indicated that the ¹⁸F-labelled fluoromethyl analogue of (+)-McN5652 has a high potential to be the tracer of choice for imaging of the serotonin transporter.