Introduction:
The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic signal transduction. Several neurodegenerative disorders like Parkinson's disease (PD) are characterised by an altered DAT availability. In the case of PD, a diminished DA biosynthesis effects a significant increase of available DAT binding sites. Radioligands for quantification of DAT availability are of high clinical relevance for early diagnosis of PD. 3-exo-phenyl tropane serves as lead structure for selective DAT ligands. LBT-999 5a, a N-4-fluorobut-2-en-1-ylated tropane derivative, exhibits excellent affinity to the DAT (K i = 9.4 nM) together with high selectivity (SERT/DAT >100 and NET/DAT >100) [1-4] . This may be due to its conformational restricted moiety at the bridge nitrogen. We intended a systematic variation of conformational restricted LBT-999 analogues to be prepared and evaluated for DAT affinity and selectivity. In addition we decided to prepare a new labelling precursor 5b for efficient direct nucleophilic fluorination.
Experimental: 2 was prepared from cocaine 1 as published elsewhere. Addition of toluene magnesium bromide and subsequent N-demethylation afforded compound 3. 3 was alkylated with appropriate ฯ-fluoro-halides to yield 5 as references. Labelling precursors were obtained via tosylation of ฯ-hydroxy analogues. 18 F was introduced via the common 18 F-cryptate procedure in moderate to high yields.
Results and Discussion: 5a and 5b have been prepared as reference and labelling precursor, respectively. Instead of the established two-step synthesis via 4-[ 18 F]fluorobut-2-en-1-yl tosylate [1,3] , a labelling precursor for direct nucleophilic radio-fluorination provides [ 18 F]LBT-999 in an easy and efficient reaction. In addition, we have prepared new conformational restricted N-substituted analogues of LBT-999. All new compounds are well suited for direct radio-fluorination and fluoroalkylation.
Conclusion:
A promising set of new tropane derivatives containing a conformational restricted C 4 -chain has been prepared to be evaluated as DAT ligands. In addition, an improved labelling precursor for efficient synthesis of [ 18 F]LBT-999 is now available for comparative small animal PET studies of dopaminergic signal pathways, involving 6-L-[ 18 F]FDOPA and [ 18 F]FP.