Cerebral dopamine D3 receptors seem to play a key role in the control of drug-seeking behavior. The imaging of their regional density with positron emission tomography (PET) could thus help in the exploration of the molecular basis of drug addiction. A fluorine-18 labeled D3 subtype selective radioligand would be beneficial for this purpose; however, as yet, there is no such tracer available. F]2a revealed high non-specific uptake in in vitro rat brain autoradiography, the D3 receptor density was successfully determined on rat brain sections (n = 4) with the candidate [ 18 F]2b offering a B max of 20.38 ± 2.67 pmol/g for the islands of Calleja, 19.54 ± 1.85 pmol/g for the nucleus accumbens and 16.58 ± 1.63 pmol/g for the caudate putamen. In PET imaging studies, the carboxamide 1 revealed low signal/background ratios in the rat brain and relatively low uptake in the pituitary gland, while the azocarboxamides [ 18 F]2a and [ 18 F]2b showed binding that was blockable by the D3 receptor ligand BP897 in the ventricular system and the pituitary gland in PET imaging studies in living rats.
18F-Labeled building blocks from the type of [18F]fluorophenylazocarboxylic-tert-butyl esters offer
a rapid, mild, and reliable method for the 18F-fluoroarylation
of biomolecules. Two series of azocarboxamides were synthesized as
potential radioligands for dopamine D3 and the μ-opioid receptor,
revealing compounds 3d and 3e with single-digit
and sub-nanomolar affinity for the D3 receptor and compound 4c with only micromolar affinity for the μ-opioid receptor,
but enhanced selectivity for the μ-subtype in comparison to
the lead compound AH-7921. A “minimalist procedure”
without the use of a cryptand and base for the preparation of 4-[18F]fluorophenylazocarboxylic-tert-butyl ester [18F]2a was established,
together with the radiosynthesis of methyl-, methoxy-, and phenyl-substituted
derivatives ([18F]2b–f). With the substituted [18F]fluorophenylazocarbylates
in hand, two prototype azocarboxylates radioligands were synthesized
by 18F-fluoroarylation, namely the methoxy azocarboxamide [18F]3d as the D3 receptor
radioligand and [18F]4a as a prototype structure of the μ-opioid receptor radioligand.
By introducing the new series of [18F]fluorophenylazocarboxylic-tert-butyl esters, the method of 18F-fluoroarylation
was significantly expanded, thereby demonstrating the versatility
of 18F-labeled phenylazocarboxylates for the design of
potential radiotracers for positron emission tomography .
There is still no efficient fluorine-18-labeled dopamine D3 subtype selective receptor ligand for studies with positron emission tomography. We aim at improving the D3 selectivity and hydrophilicity of a candidate ligand by changing the substitution pattern to a 2,3-dichlorophenylpiperazine and hydroxylation of the butyl chain. The compound [(18) F]3 exhibited D3 affinity of Ki = 3.6 nM, increased subtype selectivity (Ki (D2 /D3 ) = 60), and low affinity to 5-HT1A and α1 receptors (Ki (5-HT1A /D3 ) = 34; Ki (α1 /D3 ) = 100). The two-step radiosynthesis was optimized for analog [(18) F]4 by reducing the necessary concentration of the precursor amine (57 mM), which reacted with [(18) F]fluorophenylazocarboxylic tert-butylester under basic conditions. The optimization of the base (Cs 2 CO3 , 23 mM) and the adjustment of reaction temperature led to the radiochemical yield of 63% after 5 min at 35°C. The optimized reaction conditions were transferred on to the synthesis of [(18) F]3 with an overall non-decay corrected yield of 8-12% in a specific activity of 32-102 GBq/µmol after a total synthesis time of 30-35 min. This provides a D 3 radioligand candidate with improved attributes concerning selectivity and radiosynthesis for further preclinical studies.
Substituted indoles can be prepared from phenylazocarboxylates through a rapid one-pot sequence featuring a microwave-assisted Fischer indole synthesis as a key step. Considering that the phenylazocarboxylates may beforehand be modified by mild nucleophilic aromatic substitution, including the introduction of [ F]fluoride, the overall strategy offers an attractive new access to 5-[ F]fluoroindoles.
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