Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT(1A) activity. part 3

A number of 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine with 3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole or 2-methyl-3-(1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indole residues were synthesized for further investigation of SAR in a group of pyrido[1,2-c]pyrimidine derivatives with dual 5-HT_1A/SERT activity. Compounds 8a-8p were found to be potent ligands for both 5-HT_1A and SERT with K_i ranging from 28,3 to 642 nM and 42,4 nM-1,8 μM, respectively. Moreover compounds 8a, 8b, 8c, 8d, 8e and 8g were found to be selective agonists, while 8i as an antagonist of 5-HT_1A presynaptic receptors in the inducible hypothermia test in mice.     

Synthesis, antiviral activity, and stability of nucleoside analogs containing tricyclic bases

A series of 3,9-dihydro-9-oxo-5H-imidazo[1,2-A]purine nucleosides (tricylic nucleosides) were synthesized from 9-[4-α-(hydroxymethyl)cyclopent-2-ene-1-α-yl]guanine (CBV) 5, (−)-β-D-(2R,4R)-1,3-dioxolane-guanosine (DXG) 6, 3′-azido-3′-deoxy-guanosine (AZG) 7, and 2′-C-methylguanosine 8. Their in vitro activity against HIV and HCV was evaluated and correlated to their ability to degrade to their purine counterpart.     

Pyrroloquinolones and pyrazoloquinolones as potential antibacterial agents. Synthesis and antibacterial activity

Diethyl 1-cyclopropyl-5,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3,6-dicarboxylate 4 as a key-intermediate was synthesized via the Dieckmann reaction. The reaction of 4 with nucleophiles proceeded regioselectively at C-5. Facile cyclization between the C-5 and C-6 side chains of the resulting products gave novel pyrroloquinolones 10 and 12 and pyrazoloquinolones 15. They were converted into a series of cyclic amino-substituted pyrroloquinolones 17–21 and pyrazoloquinolones 22–24, and their in vitro antibacterial activities were tested. 1H-Pyrrolo[2,3-f]quinolone 17a and 2H-pyrrolo[3,4-f]quinolone 21a exhibited a potent in vitro antibacterial activity.     

Synthesis and in vitro antitumour activity evaluation of 1-aryl-1H,3H-thiazolo[4,3-b]quinazolines

A series of 1H,3H-thiazolo[4,3-b]quinazolines (2a–i) were synthesized and evaluated for their in vitro antitumour activity against ca. 60 human tumour cell lines. They exhibited moderate (2c, 2d, 2f and 2g) to strong (2a, 2b, 2e, 2h and 2i) cell-growth inhibition at a concentration of 10⁻⁴ M, but weak activity at lower concentrations. Only 1-(2,6-dichlorophenyl)-1H,3H-thiazolo[4,3-b]quinazoline (2h) possesses a significant growth inhibitory activity on 22 cell lines at a concentration of 10⁻⁵ M.     

Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity: Part 2

Derivatives of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine were synthesized. These compounds contain the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy or 2-methyl derivative. In vitro binding tests were performed to determine the affinity of the compounds for the 5-HT_1A receptor and serotonin transporter (SERT) proteins in the rat brain cortex. In vivo studies, particularly the inducible hypothermia test and forced swimming test, were conducted to determine agonistic/antagonistic activity with pre- and postsynaptic 5-HT_1A receptors. Molecular modeling techniques were used to determine the binding modes of the selected compounds at the 5-HT_1A receptor and SERT. The SAR analysis showed that the presence of the 3-(4-piperidyl)-1H-indole group or its 5-methoxy derivative, as well as a para substitution with –OCH₃ or –F in the aryl ring of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine, results in an increased affinity for both the 5-HT_1A receptors and SERT. In contrast, the presence of the 2-methyl-3-(4-piperidyl)-1H-indole group resulted in a considerable decrease in binding affinity.     

Synthesis and biological activity of tricyclic cycloalkylimidazo-, pyrimido- and diazepinopurinediones

Syntheses and physicochemical properties of N-cycloalkyl-substituted imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones are described. These derivatives were synthesized by cyclization of 7-halogenoalkyl-8-bromo-1,3-dimethylxanthine derivatives with aminocycloalkanes. The obtained compounds (1-33) were evaluated for their affinity to rat adenosine A₁ and A_2A receptors. Selected compounds were additionally investigated for affinity to the human A₁, A_2A, A_2B and A₃ receptor subtypes. The results of the radioligand binding assays at adenosine A₁ and A_2A receptors showed that most of the compounds exhibited adenosine A_2A receptor affinity at micromolar or submicromolar concentrations; an annelated pyrimidine ring was beneficial for A_2A affinity. The most potent A_2A ligands of the present series were compounds 6 (K_i 0.33 μM rat A_2A, 0.31 μM human A_2A), 8 (K_i 0.98 μM rat A_2A, 0.42 μM human A_2A) and 15 (K_i 0.24 μM rat A_2A, 0.61 μM human A_2A) with the latter one showing high A_2A selectivity. In NaCl shift assay, 15 was shown to be an antagonist at A_2A receptors. This result was confirmed for the best compounds 6, 8, 15 in cAMP accumulation studies. A 3D-QSAR equation with a good predicting power (q² = 0.88) for A_2A AR affinity was obtained. The compounds were evaluated in vivo as anticonvulsants in MES and ScMet tests and examined for neurotoxicity in mice (i.p.). Most of them showed anticonvulsant activity in chemically induced seizures; among them the diazepinopurinediones were the best (e.g. 31) showing protection in both tests on short time symptoms, without signs of neurotoxicity. Five compounds, 8, 17, 20, 29, and 31, exhibited anticonvulsant activity after peroral application in rats. Structure-activity relationships are discussed including the analysis of lipophilic and spatial properties. The new compounds, which contain a basic nitrogen atom and can therefore be protonated, may be good starting points for obtaining A_2A antagonists with good water-solubility.     

Synthesis and pharmacological properties of novel benzamide derivatives acting as ligands to the 5-hydroxytryptamine 4 (5-HT4) receptor

Aseries of 4-amino-5-chloro-2-methoxy-N-(1-substituted piperidin-4-ylmethyl)benzamides was synthesized as novel gastroprokinetic agents. The affinity of these compounds for the 5-hydroxytryptamine 4 (5-HT₄) receptor was evaluated. Among these compounds, 4-amino-5-chloro-2-methoxy-N-[1-[5-(1-methylindol-3-ylcarbonylamino)pentyl]piperidin-4-ylmethyl]benzamide (3f, Y-34959) showed a higher affinity for the 5-HT₄ receptor (Ki = 0.30 nmol/L) than for other receptors, and was confirmed to be a potent 5-HT₄ receptor agonist having contractile effects in the isolated guinea-pig ascending colon (EC₅₀ = 1.2 nmol/L). In dogs, compound 3f increased gastroprokinetic motility of both the gastric antrum and the ascending colon. In addition, this effect on the colon was inhibited by azasetron, a selective 5-HT₃ receptor antagonist, demonstrating that the effect of gastroprokinetic agents having 5-HT₃ receptor antagonism on the colon were reduced compared with that of selective 5-HT₄ receptor agonists.     

Inhibition of neutrophil O2 production by unsymmetrical methylene derivatives of benzopyrans: their use as potential antiinflammatory agents

Some unsymmetrical derivatives of benzopyrans 9 were synthesized and tested to verify their PKC inhibitory activity. For this purpose, the Mannich bases of 7-hydroxycoumarins 6 were treated with 2-(dialkylamino)benzopyran-4-ones or 3-(dialkylamino)naphtho[2,1-b]pyran-1-ones 8 in the presence of acetic or propionic anhydride, yielding compounds 9. Human neutrophils stimulated with either PMA and f-MLF were used as the cellular model. The efficiency of the compounds 9 was established on their capacity to reduce the O₂⁻ production by activated human neutrophils. Compounds 9d and 9f, bearing an acetoxy group in position 7 of the chromone moiety, seem to counteract the neutrophil activation efficiently.     

Synthesis of novel bioactive derivatives of 3-(4-chlorophenyl)-2-hydrazino-5,6,7,8-tetrahydrobenzo(b)thieno[2,3-d]pyrimidine-4(3H)-ones

A series of triazolo[4,3-a]tetrahydrobenzo(b)thieno[3,2-e]pyrimidine-5(4H)-ones (12a–n) were synthesized and evaluated for CNS depressant, skeletal muscle relaxant and anticonvulsant activities by photoactometer, Rotarod and pentylenetetrazole induced the convulsions method respectively in Swiss albino mice. Diazepam was used as standard drug. The five derivatives 12b, 12c, 12d, 12i and 12m showed the CNS depressant and skeletal muscle relaxant activities comparable to those of diazepam at a dose of 5 mg/kg. These derivatives also exhibited good activity when tested for anticonvulsant activity in mice at different dose levels. The ED₅₀ values for these derivatives are in the range of 4.40–9.33 mg/kg.     

Anti-Pneumocystis carinii pneumonia activity of dicationic diaryl methylprimidines

Synthesis of 2,4-bis-(4-amidinophenyl)-6-methylpyrimidine 5, 2,4-bis-[(4-imidazolin-2-yl)phenyl]-6-methylpyrimidine 6, 2,4-bis[(4-N-i-propylamidino)phenyl]-6-methylpyrimidine 7, and 2,4-bis[(4-N-isopentylamidino)phenyl]-6-methylpyrimidine 8 starting from 4-bromobenzamidine and 4′-bromoacetophenone is reported. The synthesis of 2,4-bis-(4-amidinophenyl)-5-methylpyrimidine 12 and 2,4-bis-[(4-imidazolin-2-yl)phenyl]-5-methylpyrimidine 13, also beginning with 4-bromobenzamidine and 4′-bromopropiophenone is described. A synthesis of 4,6-bis-(4-amidinophenyl)-2-methylpyrimidine 17, 4,6-bis-[(4-imidazolin-2-yl)phenyl]-2-methylpyrimidine 18, 4,6-bis[(4-N-i-propylamidino)phenyl]-2-methylpyrimidine 19 and 4,6-bis[(4-N-n-propylamidino)phenyl]-2-methylpyrimidine 20 starting from acetamidine and 1,3-bis(4-bromophenyl)propenone is reported. Compounds 5–7 and 17–20 all bind strongly to the minor groove of poly-dA-dT whereas 8, 12 and 13 bind less tightly as judged by their ΔT_in values. A similar trend was noted for binding of these compounds to the 12-mer-d(CGCGAATTCGCG)₂. Compounds 5, 7, and 17 are more active and less toxic than pentamidine at its effective dose when evaluated against Pneumocystis carinii pneumonia (PCP) in the immunosuppressed rat model.     

Pyrimido[5,4-b]benzofuran and pyrimido[5,4-b]benzothiophene derivatives Ligands for α1-and 5HT1A-receptors

A number of 3-phenylpiperazinylethyl pyrimido[5,4-b]benzofuran-2,4-dione and pyrimido[5,4-b]benzothiophene-2,4-dione derivatives 5–15 were designed as bioisosters of the previously reported pyrimido[5,4-b]indole-2,4-diones and synthesized starting from the 3-amino-2-carboxybenzofuran and benzothiophene ethyl and methyl esters respectively. They were evaluated for their in vitroα₁-adrenoceptor and 5HT_1A-receptor affinities by radioligand receptor binding assays. All target compounds showed good to excellent affinities for the α₁-adrenoceptor with K_i values in the subnanomolar range. Some compounds were also good ligands for the 5HT_1A-receptor with K_i values in the nanomolar range. 3-[2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl]-1-methyl pyrimido[5,4-b]benzothiophen-2,4-dione 15 was the most active derivative in displacing [³H]-8-OH-DPAT from rat hippocampal membranes. There is evidence suggesting that the N₁ methyl group of the tricyclic moiety of the title compounds is probably able to undergo a Van der Waals interaction at the 5HT_1A-receptor binding site but not at the α₁-adrenoceptor active site.     

Synthesis of some novel pyrazolo[3,4-b]pyridine and pyrazolo[3,4-d]pyrimidine derivatives bearing 5,6-diphenyl-1,2,4-triazine moiety as potential antimicrobial agents

The reaction of 5,6-diphenyl-3-hydrazino-1,2,4-triazine (1) with bis(methylthio)methylene]malononitrile (2) afforded 5-amino-1-(5,6-diphenyl-1,2,4-triazin-3-yl)-3-(methylthio)-1H-pyrazole-4-carbonitrile (3). Compound 3 reacted with thiourea to give 3,4-diaminopyrazolo[3,4-d]pyrimidine 5, which was treated with benzoyl chloride to give pyrazolo[5,4,3-kl]pyrimido[4,3-d]pyrimidine 6. Treatment of 3 with acetic anhydride produced 3-methylthio-pyrazolo[3,4-d]pyrimidine derivative 7, which was allowed to react with hydrazine hydrate to give the corresponding hydrazino derivative 8. Heterocyclization of 8 with benzoyl chloride and sodium pyruvate afforded the polyfused heterocycles 9 and 10, respectively. Reaction of 3 with benzoylacetone yielded pyrazolo[3,4-b]pyridine 12, which was allowed to react with malononitrile and acetanilide to get heterocyclic systems 13 and 14, respectively. Interaction of 3 with cyanoacetone gave pyrazolo[3,4-b]pyridine 15, which was refluxed in formic acid to yield pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidine 16. Reaction of 3 with 2 afforded the triazinylpyrazole derivative 17, which was reacted with hydrazine hydrate to give dipyrazolo[1,5-a:3′,4′-d]pyrimidine 19. Furthermore, treatment of the latter compound with methyl anthranilate furnished tetraheterocyclic compound 21. Structures of the products have been determined by elemental analysis and spectral studies. All compounds have been screened for their antibacterial and antifungal activities. Compounds 9, 10, 13, 19 and 21 showed maximum activity comparable to the standard drugs with lower toxicity in the case of 9 and 10.     

Synthesis and inhibition study of monoamine oxidase, indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase by 3,8-substituted 5H-indeno[1,2-c]pyridazin-5-one derivatives

Previous studies on 5H-indeno[1,2-c]pyridazin-5-one derivatives as inhibitors of MAO-B revealed that it was possible to increase the MAO-B inhibitory potency of 5H-indeno[1,2-c]pyridazin-5-ones by substituting the central heterocycle in the 3-position or C-8 with lipophilic groups which occupy the substrate cavity or the entrance of the binding site, respectively. Here, four new 5H-indeno[1,2-c]pyridazin-5-one derivatives containing lipophilic groups at both positions were synthesized and their inhibitory potency against human monoamine oxidase A and B were evaluated. Selectivity of these compounds against IDO and TDO, two enzymes sharing substrate similarity with MAO and involved in the serotonergic and kynurenine pathways was also studied. All compounds showed higher activity and selectivity against MAO-B, the most effective one being 3-methyl-8-meta-chlorobenzyloxy-5H-indeno[1,2-c]pyridazin-5-one (9a) which was shown to be a competitive inhibitor with a K_i value of 0.11 μM. Replacing the methyl group in the 3-position with a meta–CF₃–phenyl group (7a, 7b and 7c) abolished the inhibitory potency against MAO-B. Indeed, the substitution of the 5H-indeno[1,2-c]pyridazin-5-one core in the 3-position dramatically influences the MAO-inhibiting properties of these compounds. Molecular docking studies of 9a within MAO-B suggest that the 5H-indeno[1,2-c]pyridazin-5-one scaffold is well stabilized into the substrate cavity with the meta-chlorobenzyloxy side chain extending towards a rather hydrophobic pocket at the entrance cavity.     

Synthesis, characterization and antibacterial activity of 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazoles

In the present investigation a series of novel 2-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazol-4-yl]-5-(substituted-phenyl)-[1,3,4]oxadiazoles (4a–j) were synthesized by cyclization of substituted-benzoic acid N′-[1-(5-chloro-2-methoxy-phenyl)-5-methyl-1H-pyrazole-4-carbonyl]-hydrazide by using phosphorousoxychloride at 120 °C. The chemical structure of the newly synthesized compounds was characterized by analytical and spectral (IR, ¹H NMR, ¹³C NMR and LC–MS) methods. The title compounds were screened for qualitative (zone of inhibition) and quantitative antibacterial activity (MIC) by agar cup plate and microtitration methods, respectively. Among the synthesized compounds in this series compound 2-[1-(5-chloro-2-methoxyphenyl)-5-methyl-1H-pyrazol-4-yl]-5-(4-fluorophenyl)-1,3,4-oxadiazole (4b) was found to exhibit significant antibacterial activity with MICs of 22.4, 29.8, 29.6 and 30.0 μg/mL against Bacillus subtilis, Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae, respectively. The other compounds exhibited moderate activity when compared to standard substance Ampicillin.     

Synthesis of 4H-chromene, coumarin, 12H-chromeno[2,3-d]pyrimidine derivatives and some of their antimicrobial and cytotoxicity activities

Condensation of 3-N,N-diethylaminophenol (1) with α-cyanocinnamonitriles (2a-c) and ethyl α-cyanocinnamates (2d-f) provided compounds 3a-f and 4a-c. 12H-Chromeno[2,3-d]pyrimidine derivatives 6, 11-13 and 16 were obtained by treatment of 4H-chromene compounds (3) with different electrophiles followed by nucleophilic reagents. Structures of these compounds were established on the basis of IR, UV, ¹H NMR, ¹³C NMR and MS data. Some of the new compounds were evaluated for antimicrobial and cytotoxicity activities.     

Synthesis, photochemical E (trans) → Z (cis) isomerization and antimicrobial activity of 2-chloro-5-methylpyridine-3-olefin derivatives

2-Chloro-5-methylpyridine-3-olefin derivatives (3a-e) have been synthesized from 2-chloro-5-methylnicotinaldehyde (1) and studied their photochemical E (trans) → Z (cis) isomerization upon direct irradiation and triplet sensitized excitation for the first time. The triplet sensitized excitations of the compounds yielded high Z (4a–e) isomer composition, whereas the direct excitation results in less Z (4a–e) isomer composition, indicating triplet pathway is very efficient in converting the E (trans) → Z (cis) isomer. Thus synthesized E (3a–c and 3e) and generated Z (4a–c and 4e) isomers were tested for antimicrobial activity. Antifungal activity of these pyridine derivatives are closely comparable to the standard used.     

Synthesis and anticonvulsant activity of some new thiazolo[3,2-a][1,3]diazepine, benzo[d]thiazolo[5,2-a][12,6]diazepine and benzo[d]oxazolo[5,2-a][12,6]diazepine analogues

A new series of 6,7-dihydro-thiazolo[3,2-a][1,3]diazepines (9–12), benzo[d]thiazolo[5,2-a][12,6]diazepines (19–21) and benzo[d]oxazolo[5,2-a][12,6]diazepine (24) analogues were synthesized and evaluated for their anticonvulsant activity. Compounds (E)-2-bromo-6,7-dihydro-thiazolo[3,2-a][1,3]diazepine-8(5H)-thione (12), 3-chloro-benzo[d]thiazolo[5,2-a][12,6]diazepin-10-one (20), and 4-chloro-benzo[d]oxazolo[5,2-a][12,6] diazepin-10-one (24) showed 100% protection against PTZ- and bicuculline-induced seizures; 70%, 33%, 70% protection against MES-induced tonic extension; and 70%, 66%, 100% protection against picrotoxin-induced convulsions, respectively. Compounds 12, 20, and 24 proved to act as GABA_A receptor agonists, with ED₅₀ values of 252, 380, 251 mg/kg; TD₅₀ values of 398, 417, 355 mg/kg; PI values of 1.58, 1.09, 1.41; LD₅₀ values of 380, 617, 537 mg/kg and TI values of 1.51, 1.62, 2.14, respectively.     

Imidazo[1,2-a]quinoxalin-4-amines: A novel class of nonxanthine A1-adenosine receptor antagonists

The syntheses and A₁ adenosine receptor affinities of a number of imidazo[1,2-a]quinoxalin-4-amines are reported. Structure—activity relationships within the series and in comparison with other similar tricyclic nonxanthine adenosine antagonists are discussed, leading to a putative common binding mode of these nitrogen-containing heterocycles to A₁ adenosine receptors. Secondary amino compounds displayed the best affinities toward A₁ receptors, while the tertiary amines were almost devoid of activity, thus suggesting a crucial role for the hydrogen bond-forming 4-NH group. Remarkably higher potencies for 1-methyl and N-cyclopentyl derivatives were also found. 4-Cyclopentylamino-1-methylimidazo[1,2-a]quinoxaline (TRFI 165) is the most potent compound in this series, having K_i(A₁) = 7.9 nM. It is also provided with a good A₁ selectivity both versus A_2a and A₃ subtypes and was selected for further pharmacological studies.     

Synthesis and anticonvulsant activity of 8-alkoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one derivatives

A series of novel 8-alkoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The results of these tests demonstrated that 8-heptyloxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3f) and 8-hexyloxy -5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3e) were the most promising compounds, with median effective dose (ED₅₀) of 17.6 and 17.9 mg/kg, and protective index (PI) of greater than 63.4 and 62.4 in the MES test, respectively. These PI values were higher than the PI value of the prototype antiepileptic drug carbamazepine. The scPTZ test showed that 8-pentyloxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3d) was the most potent with ED₅₀ value of 38.0 mg/kg and PI value of greater than 29.4, which is much safer than marketed drug carbamazepine. The possible structure-activity relationship was discussed.     

Design, synthesis and in vitro evaluation of bridgehead fluoromethyl analogs of N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635) for the 5-HT(1A) receptor

Fluorinated analogs that are related to the 5-hydroxytryptamine (5-HT_1A) antagonist, N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635), have been synthesized and their binding affinity for the 5-HT_1A receptor and other neurotransmitter receptors (adrenoceptors, sigma receptors, and dopamine receptors), and serotonin transporters was examined in vitro. These ligands were designed to provide a possible potential positron emission tomography (PET) ligand with high metabolic stability. To this end, the cyclohexyl moiety in WAY-100635 and in O-desmethyl WAY-100635 was replaced by a bridge-fused ring (BFR) such as adamantyl, cubyl, bicyclo[2.2.2]octyl and bicyclo[2.2.1]heptyl to reduce the metabolic rate of the amide bond hydrolysis, while a fluoromethyl group was introduced on the other bridgehead of the BFR to prevent defluorination by HF elimination. All synthesized analogs displayed high affinity in the (sub)nanomolar range for the 5-HT_1A receptor, comparable to WAY-100635. In addition, 6b, 6c and 6d were reasonably selective to the 5-HT_1A receptor over the above mentioned receptors. In human hepatocytes, 6b showed a suitable metabolic stability.In conclusion, the obtained data provides a promising starting point for the synthesis of the corresponding ¹⁸F-labeled PET analogs.