¹⁸F‐Labeled FAUC 346 and BP 897 Derivatives as Subtype‐Selective Potential PET Radioligands for the Dopamine D3 Receptor

Abstract

Disturbances of neutrotransmission at the dopamine D3 receptor are related to several neuropsychiatric diseases and in particular to drug addiction. Herein, we report the computer-assisted prediction of D3 selectivities of new fluoroalkoxy-substituted receptor ligands by means of 3D-QSAR analysis. As close analogues of the D3-selective lead compound FAUC 346 and BP 879, the (19)F-substituted test compounds 4 a-d were synthesized and evaluated. In vitro investigation of their binding characteristics in transfected Chinese Hamster Ovary (CHO) cells led to excellent K(i) values between 0.12 and 0.69 nM at the dopamine D3 subtype. The benzothiophene-substituted carboxamide 4 a (K(i)=0.12 nM) displayed 133 and 283-fold selectivity over the structurally related D2(Long) and D4 subtypes, respectively. Mitogenesis assays showed the behavior of partial agonists. Based on these data, we synthesized the [(18)F]fluoroethoxy-substituted radioligands [(18)F]4 a-d. The N-[4-[4-(2-hydroxyphenyl)piperazin-1-yl]butyl]-2-carboxamides 3 a-d were prepared and labeled with 2-[(18)F]fluoroethyltosylate in a two-step procedure. Optimization of the (18)F-labeling conditions led to radiochemical yields between 24 and 65 %.

A Series of 18F‐Labelled Pyridinylphenyl Amides as Subtype‐Selective Radioligands for the Dopamine D3 Receptor

“…[26,27] The 11 C-labelled candidate has been studied in vivo and revealed specific uptake in the rat brain, however, the regional brain distribution has not yet been determined. Despite the promising results in the rat model, 11 C-labelled FAUC 346 failed as a suitable PET radioligand for imaging of D3 receptors in baboon, as the intravenous injection of BP 897 did not affect the brain uptake of the radioligand.…”

Development of molecular tools based on the dopamine D3 receptor ligand FAUC 329 showing inhibiting effects on drug and food maintained behavior

“…Based on our previous work on the preparation of [ 18 F]2 in an analytical scale, 30 it was our intention here to optimize the radiosynthesis for extended in-vitro and in-vivo PET imaging studies. To accomplish this goal, we envisaged the synthesis of a suitable tosylate labeling precursor for an efficient one-step nucleophilic 18 F-fluorination that would provide direct access to [ 18 F]2 .…”

“…28, 29 Compound 1 demonstrated significant neuroprotective effects on dopamine depletion, which was most pronounced in the nucleus accumbens according to the preferential abundance of D 3 receptors in this region. A preparation of [ 18 F]2 on an analytical scale had been previously published, 30 however, the radiotracer has not yet been investigated for imaging purposes.…”

Graphical Abstract: ChemMedChem 5/2008

“…Synthesis of an Original Oxygenated Taxuspine X Analogue: a Versatile "Non-Natural" Natural Product with Remarkable P-gp Modulating Activity An efficient synthetic strategy has been developed to prepare an oxygenated analog of Taxuspine X. Macrocycle formation through Yamaguchi macrolactonization approach gave access to an original compound (18) showing remarkable P-gp modulating activity. Further functionalization of this versatile scaffold could lead to potential anticancer and/or MDR reversing agents.…”