Synthesis and SERT Binding Properties of 5-Fluoroindol-3-yl cyclobutylamines

Several mental diseases are associated with disorders of the serotonergic neurotransmission.[1] The serotonin transporter (SERT) regulates the synaptic concentration of this neurotransmitter and represents a primary target in the development of antidepressant drugs. Indol-3-yl-cyclo-alkanyl/-alkenyl amines (CnH2n-2(4), n=6,5,3), considered as conformationally constrained analogues of 5-hydroxytryptamine (5-HT, serotonin), have been introduced as a class of candidates holding highly potent SERT inhibitors[.2] In the search for new SERT ligands for PET with improved binding profiles we turned our interest towards rigid structures containing a 1,3-disubstituted cyclobutane (CnH2n-2, n=4), as spacer between the indole moiety and the amino group.
The present work describes our work on the synthesis and biological evaluation of the mono-fluorinated (2a,3a,4a) and double-fluorinated target molecules (1 b,2b).
The carbonyl group of both 3-(2-benzyloxy-ethyl)- and 3-(3-benzyloxy-propyl)cyclobutanone was converted by appropriate steps to yield the N-methyl, N-Boc protected cis- or trans-cyclobutyl amines. After removing the O-benzyl group, the alcohol was oxidized to the aldehyde applying the known TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) procedure. The secondary amines (1a-4a) were then directly obtained from the cyclobutyl aldehyde precursor via Fischer indole synthesis; for the tertiary amines 1 b and 2b an N-alkylation of 1 a and 2a with 3-fluoropropyliodide was performed.
Displacement experiments on hSERT-HEK293 cells labeled with [3H]citalopram have shown that cis-derivatives (Ki values: 1 b, 6.74±0.79 nM; 2a, 5.43±0.54 nM; 2b, 6.31 ±1 .37 nM) have nanomolar affinity for human SERT. The trans compound shows somewhat lower affinity (3a, 10.7±1.88 nM). By contrast, parallel studies applying [3H]paroxetine as radioligand indicated significantly lower SERT affinities [90 nM < Ki (1 b,2a,2b,3a,4a) <155 nM]. Thus, potential radiotracers based on the new derivatives may be able to selectively label the citalopram binding site of the SERT.
We have developed a general access to 5-fluoroindol-3-yl cyclobutylamines both in cis(1a, 1b, 2a, 2b) and trans-configuration (3a, 4a) obtained from readily accessible starting materials. Five synthesized compounds (1b, 2a, 2b, 3a, 4a) displayed promising affinities for SERT.