Synthesis and radiopharmacological characterization of 2β-carbo-2′-[ 18F]fluoroethoxy-3β-(4-bromo-phenyl)tropane ([ 18F]MCL-322) as a PET radiotracer for imaging the dopamine transporter (DAT)

Abstract

The fluoroalkyl-containing tropane derivative 2β-carbo-2′-fluoroethoxy-3β-(4-bromo-phenyl)tropane (MCL-322) is a highly potent and moderately selective ligand for the dopamine transporter (DAT). The compound was labeled with the short-lived positron emitter 18F in a single step by nucleophilic displacement of the corresponding tosylate precursor MCL-323 with no-carrier-added [ 18F]fluoride. The positron emission tomography (PET) radiotracer 2β-carbo-2′-[ 18F]fluoroethoxy-3β-(4-bromo-phenyl)tropane [ 18F]MCL-322 was obtained in decay-corrected radiochemical yields of 30–40% at a specific radioactivity of 1.6–2.4 Ci/μmol (60–90 GBq/μmol) at the end-of-synthesis (EOS). Small animal PET, ex vivo and in vivo biodistribution experiments in rats demonstrated a high uptake in the striatum (3.2% ID/g) 5 min after injection, which increased to 4.2% ID/g after 60 min. The uptake in the cerebellum was 1.8% ID/g and 0.6% ID/g after 5 min and 60 min post-injection, respectively. Specific binding to DAT of [ 18F]MCL-322 was confirmed by blocking experiments using the high affinity DAT ligand GBR 12909. The radiopharmacological characterization was completed with metabolite and autoradiographic studies confirming the selective uptake of [ 18F]MCL-322 in the striatum. It is concluded that the simple single-step radiosynthesis of [ 18F]MCL-322 and the promising radiopharmacological data make [ 18F]MCL-322 an attractive candidate for the further development of a PET radiotracer potentially suitable for clinical DAT imaging in the human brain.