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.

Graphical abstract

The simple single-step radiosynthesis and radiopharmacological characterization of [¹⁸F]MCL-322 as novel radiotracer for imaging DAT is described.

Keywords: [¹⁸F]MCL-322; Dopamine transporter (DAT); Positron emission tomography (PET)

Article Outline

1. Introduction

2. Results

2.1. Radiochemistry

2.2. [¹⁸F]MCL-322 biodistribution in peripheral organs

2.3. Ex vivo autoradiography in rat brain

2.4. [¹⁸F]MCL-322 metabolites

2.5. Small animal PET and MRI

3. Discussion

4. Conclusion

5. Materials and methods

5.1. Radiochemistry

5.1.1. Preparation of 2β-carbo-2′-[¹⁸F]fluoroethoxy-3β-(4- bromophenyl)tropane ([¹⁸F]MCL-322)

5.2. Biodistribution studies in rats

5.3. Ex vivo autoradiography

5.4. Metabolite analysis

5.5. PET imaging

5.6. microMRT imaging

5.7. Statistical analysis

Acknowledgements

References