Ring-Opening of 3-β-D-Ribofuranosyl-3,7,8,9-Tetrahydropyrimido [1,2-i]Purin-8-ol and Preparation of 2-Thio- and 2-aza-Adenosine Derivatives

The adduct 3-β-D-ribofuranosyl-3,7,8,9-tetrahydropyrimido[1,2-i]purin-8-ol (2), obtained from adenosine and epichlorohydrin, underwent ring fission at basic conditions. The initial ring-opening took place at C2 of the pyrimidine unit resulting in 2-(5-amino-1-β-D-ribofuranosyl-imidazol-4-yl)-1,4,5,6-tetrahydropyrimidin-5-ol (3). Also the tetrahydropyrimidine ring of 3 could be opened resulting in 5-amino-1-(β-D-ribofuranosyl)-imidazole-4-(N-3-amino-2-hydroxyl-propyl)-carboxamide (4). In hot acid conditions, 2 was both deglycosylated and ring-opened yielding 2-(5-amino-imidazol-4-yl)-1,4,5,6-tetrahydropyrimidin-5-ol (7) as the final product. When reacting 3 with CS₂ or HNO₂ ring-closure took place and 3-β-D-ribofuranosyl-3,4,7,8,9-pentahydropyrimido[1,2-i]purin-8-ol-5-thione (5), and 3-β-D-ribofuranosyl-imidazo[4,5-e]-3,7,8,9-tetrahydropyrimido[1,2-c][1,2,3]triazine-8-ol (6), respectively, were obtained. Also, the pyrimidine ring of the epichlorohydrin adduct with adenine, 10-imino-5,6-dihydro-4H,10H-pyrimido[1,2,3-cd]purin-5-ol (10), underwent ring fission and the product was identified as 3-hydroxy-1,2,3,4-tetrahydroimidazo[1,5-a]pyrimidine-8-carboximidamide (11).     

Convenient Syntheses of 6-Methylpurine and Related Nucleosides

Abstract

Efficient methods for the synthesis of 6-methylpurine (3), 9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-methylpurine (8), and 6-methyl-9-β-D-ribofuranosylpurine (5) are described. Methodology involving the (Ph₃P)₄Pd catalyzed cross-coupling reaction of CH₃ZnBr with several different 6-chloropurine derivatives is described in high yield. This methodology now provides a facile and high-yielding synthesis of 8, which is needed in significant amounts for studies in cancer gene therapy.     

Nucleosides and Nucleotides. 192. Toward the Total Synthesis of Cyclic ADP-Carbocyclic-Ribose. Formation of the Intramolecular Pyrophosphate Linkage by a Conformation-Restriction Strategy in a Syn-form Using a Halogen Substitution at the 8-Position of the Adenine Ring

Abstract

The synthesis of cyclic ADP-carbocyclic-ribose (2), as a stable mimic for cyclic ADP-ribose, was investigated. Construction of the 18-membered backbone structure was successfully achieved by condensation of the two phosphate groups of 19, possibly due to restriction of the conformation of the substrate in a syn-form using an 8-chloro substituent at the adenine moiety. SN2 reactions between an optically active carbocyclic unit 8, which was constructed by a previously developed method, and 8-bromo-N ⁶-trichloroacetyl-2′,3′-O-isopropylideneadenosine 9c gave N-1-carbocyclic derivative, which was deprotected to give 5′,5′-diol derivatives 18. When 18 was treated with POCl₃ in PO(OEt)₃, the bromo group at the 8-position was replaced to give N-1-carbocyclic-8-chloroadenosine 5′,5′-diphosphate derivative 19 in 43% yield. Treatment of 19 with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride gave the desired intramolecular condensation product 20 in 10% yield. This is the first chemical construction of the 18-membered backbone structure containing an intramolecular pyrophosphate linkage of a cADPR-related compound with an adenine base.     

Synthesis and antibacterial properties of new N4-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids

Direct interaction between 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and primary α-amino acids (exemplified by glycine, alanine, and l-valine) in aqueous ethanolic NaHCO₃ at 70–80°C for 24–72?h produced the respective N-(4-oxoquinolin-7-yl)-α-amino acids (6a–c). The latter derivatives underwent reductive lactamization upon treatment with Na₂S₂O₄ in aqueous ethanol to afford moderate yields of the corresponding pyrido[2,3-f]quinoxaline-8-carboxylic acids (8a–c). Acetylation of 8a–c using acetyl chloride afforded N₄-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids (9a–c). The structures, assigned to these new heterocyclic products, are supported by analytical and spectral data. The synthesized compounds (6a–c/9a–c) showed appreciable antibacterial activity as compared with ciprofloxacin.     

Synthesis of Hydantoin Nucleosides with Naphthylmethylene Substituents in the 5-Position

Abstract

(Z)-5-(Naphthylmethylene)-2-thiohydantoin derivatives (3a,b,12a-d) were prepared directly fiom condensations of 2-thiohydantoin derivatives (1,l la,b) with naphthaldehydes. Bisglycosylation took place on reaction of (Z)-5-(naphthylmethylene)- 2-thiohydantoin derivatives (3a,b) with glycosyl halides (4a,b) under alkaline conditions. The bisglycosilated hydantoins produced N₃ glycosylated hydantoins on treatment with ammonia in methanol. (Z)-5-(2-Naphthylmethylene)-2-(benzylidene E-hydrazono)hydantoin (9a) and (Z)-5-(2-naphthylmethylene)-2-(polyhydroxyalkylidene E-hydrazono)hydantoins (9b,c) were prepared fiom the reaction of (Z)-5-(2-naphthyylmethylene)-2- methylmercaptohydantoin (7) with benzylidene E-hydrazone (8a) and monosaccharide E-hydrazones (8b,c). S-Glycosylation also took place when N₃ substituted hydantoins were reacted. The hydantoin nucleosides were tested for their potential activity against HTV and HSV.     

Biological exploration of a novel 1,2,4-triazole-indole hybrid molecule as antifungal agent

Abstract

(2-(2,4-Dichlorophenyl)-3-(1H-indol-1-yl)-1-(1,2,4-1H-triazol-1-yl)propan-2-ol (8?g), a new 1,2,4-triazole-indole hybrid molecule, showed a broad-spectrum activity against Candida, particularly against low fluconazole-susceptible species. Its activity was higher than fluconazole and similar to voriconazole on C. glabrata (MIC₉₀ = 0.25, 64 and 1?µg/mL, respectively), C. krusei (MIC₉₀ = 0.125, 64 and 0.125?µg/mL, respectively) and C. albicans (MIC₉₀ = 0.5, 8 and 0.25?µg/mL, respectively). The action mechanisms of 8?g were also identified as inhibition of ergosterol biosynthesis and phospholipase A2-like activity. At concentration as low as 4 ng/mL, 8g inhibited ergosterol production by 82% and induced production of 14a-methyl sterols, that is comparable to the results obtained with fluconazole at higher concentration. 8?g demonstrated moderate inhibitory effect on phospholipase A2-like activity being a putative virulence factor. Due to a low MRC5 cytotoxicity, this compound presents a high therapeutic index. These results pointed out that 8?g is a new lead antifungal candidate with potent ergosterol biosynthesis inhibition.     

Boronated phosphonium salts containing arylboronic acid, closo-carborane, or nido-carborane: synthesis, X-ray diffraction, in vitro cytotoxicity, and cellular uptake

The preparation of boronated triaryl and tetraaryl phosphonium salts of the type [PPh₃CH₂R]Br [R is 4-boronophenyl (1), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (2), 3-boronophenyl (3), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (4), 2-boronophenyl (5), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-yl)phenyl (6), and closo-1,2-carboran-1-yl (7)] is described. These compounds were prepared by the reaction of triphenylphosphine with benzylic bromides or 1-bromomethyl-closo-1,2-carborane in acetonitrile solution at 85 °C. The zwitterionic nido-7,8-carborane derivative PPh₃CH₂C₂B₉H₁₁ (8) was prepared by treatment of 7 with cesium fluoride in refluxing ethanol. All compounds were fully characterized by multinuclear (¹H, ¹¹B, ¹³C, and ³¹P) 1D- and 2D-NMR spectroscopy, electrospray ionization mass spectrometry, and elemental analysis, and single-crystal X-ray structures were determined for compounds 1, 3, 7, and 8. The cytotoxicities and boron uptake of selected derivatives were investigated in vitro using human glioblastoma (T98G) and canine kidney tubule (MDCK II) cells. The zwitterionic species 8 was found to be the least cytotoxic agent while also delivering the greatest amount of boron to the T98G cells, peaking at 9.15 ± 2.65 μg B/mg protein.     

Synthesis of octyl S-glycosides of tri- to pentasaccharide fragments related to the GPI anchor of Trypanosoma brucei

The three oligosaccharide octyl-S-glycosides Man-α1,6-Man-α1,4-GlcNH₂-α1,S-Octyl (19), Man-α1,6-(Gal-α1,3)Man-α1,4-GlcNH₂-α1,S-Octyl (27) and Man-α1,2-Man-α1,6-(Gal-α1,3)Man-α1,4-GlcNH₂-α1,S-Octyl (37), related to the GPI anchor of Trypanosoma brucei were prepared by a stepwise and block-wise approach from octyl 2-azido-2-deoxy-3,6-di-O-benzyl-1-thio-α-d-glucopyranoside (8) and octyl 2-O-benzoyl-4,6-O-(1,1,3,3-tetraisopropyl-1,3-disiloxane-1,3-diyl)-1-thio-α-d-mannopyransoside (9). Glucosamine derivative 8 was obtained from 1,3,4,6-tetra-O-acetyl-2-azido-2-desoxy-β-d-glucopyranose (1) in five steps. Mannoside 9 was converted into the corresponding imidate 12 and coupled with 8 to give disaccharide octyl-S-glycoside 13 which was further mannosylated to afford trisaccharide 19 upon deprotection. Likewise, mannoside 9 was galactosylated, converted into the corresponding imidate and coupled with 8 to give trisaccharide 25. Mannosylation of the latter afforded tetrasaccharide 27 upon deprotection. Condensation of 25 with disaccharide imidate 35 gave, upon deprotection of the intermediates, the corresponding pentasaccharide octyl-S-glycoside 37. Saccharides 19, 27 and 37 are suitable substrates for studying the enzymatic glycosylation pattern of the GPI anchor of T. brucei.     

Lysine Dendrimers and Their Starburst Polymer Derivatives: Possible Application for DNA Compaction and in vitro Delivery of Genetic Constructs

We attempted to find some compounds for the effective delivery of gene constructs into cells and obtained two trispherical dendrimers on the basis of lysine, (Lys)₈-(,-Lys)₄-(,-Lys)₂-(,-Lys)-Ala-NH₂ (D1) and ((Lys)₈-(,-Lys)₄-(,-Lys)₂-,-Lys)-Ala-[Lys(Plm)]₂-Ala-NH₂ (D2), as well as the starburst polymeric derivatives of D1, (pVIm) ₈ -D1 and (pLys) _n -D1, containing poly(N-vinylimidazole) and polylysine chains single-point bound to the dendrimer amino groups. The conditions of dendrimer–plasmid DNA complex formation were studied. The intracellular localization of these complexes and the expression of gene constructs delivered with their help were analyzed in transfection experiments on the HeLa cell cultures of human epithelial carcinoma and on mouse C2C12 myoblasts. It was found that the chemical structure of dendrimer D1 and its derivatives significantly affected the structure and properties of complex.     

Different effects of cGMP and cAMP in the intestine of the European eel,Anguilla anguilla

The regulation of salt absorption in the sea water cell intestine was studied by evaluating the effects of theophylline, 8 Br cyclic adenosine monophosphate, 8 Br cyclic guanosine monophosphate, atriopeptin III, porcine vasoactive intestinal peptide and prostaglandin E ₁ on the short-circuit current, the transepithelial voltage difference and conductance and on the dilution potentials. It was shown that theophylline increased the transepithelial conductance and reduced the magnitude of the dilution potentials, indicating that the drug increase the anion conductance of the tight junctions. In addition its inhibitory effect on short-circuit current and transepithelial voltage difference suggests that theophylline also affects the transcellular transport mechanisms. It was shown that 8 Br cyclic guanosine monophosphate and 8 Br cyclic adenosine monophosphate affect transcellular mechanisms underlying Cl^– transport since both compounds reduced short-circuit current and transepithelial voltage difference; however, cyclic adenosine monophosphate is less effective since unlike cyclic guanosine monophosphate, even at maximal concentration, it was not able to completely abolish transepithelial voltage difference and short-circuit current. The effects of cyclic guanosine monophosphate and cyclic adenosine monophosphate were not additive even if cyclic guanosine monophosphate may produce further inhibition of ion transport in 8 Br cyclic adenosine monophosphate-treated tissues. In addition, cyclic guanosine monophosphate but not cyclic adenosine monophosphate reduced the magnitude of the dilution potentials, suggesting that cyclic guanosine monophosphate acts also on the paracellular pathway. Rat atriopeptin III, a peptide known to increase cyclic guanosine monophosphate cellular levels, behaved like 8 Br cyclic guanosine monophosphate since it lowered the dilution potentials and reduced short-circuit current and transepithelial voltage difference to near zero values, suggesting that the hormone modulates both paracellular and transcellular transport mechanisms, probably acting on the Na-K-2Cl cotransport. Agents acting via cyclic adenosine monophosphate, like porcine vasoactive intenstinal peptide and prostaglandin, behaved like 8 Br cyclic adenosine monophosphate. They were less effective in inhibiting ion transport and did not interfere with the paracellular pathway.Abbreviations AP III rat artriopeptin III - 8 Br cAMP 8 Br cyclic adenosine monophosphate - 8 Br cGMP 8 Br cyclic guanosine monophosphate - g _t transepithelial conductance - I _sc short circuit current - IC ₅₀ half-maximal inhibitory concentration - NaK ATPase Na-K-adenosine monophosphate - NPPB 5-nitro-2-(3-phenylpropylamino)-benzoic acid - PGE prostaglandin E ₁ - R _t tissue resistance - SITS 4-acetamide-4-isothiocyano-stilbene-2,2-disulfonic acid - V _t transepithelial voltage difference - VIP porcine vasoactive intestinal peptide     

Reactions of Some 2,3-Anhydro Pyrimidine Nucleosides with Dilithium Tetrahalocuprates

Abstract

The reaction of 1-(2,3-anhydro-5-0-trityl-β-D-lyxofuranosyl)-2-0-methyluracil (2a) and its thymine analogue (2b) with dilithium tetrahalocuprates (Li₂CuX₄) revealed an excellent to perfect regioselectivity, yielding 2,2′-anhydro-3′-halonucleosides (3a-d), while the same reactions with 2,3-anhdro uracil and thymine nucleosides (5a,b) gave arabinosyl (6a-d) and xylosyl halohydrins (7a-d) with respective product ratios of 7:3 to 8:2 which were estimated after mesylation to 8a-d and 9a-d.     

Antitumor evaluation and molecular docking study of substituted 2-benzylidenebutane-1,3-dione, 2-hydrazonobutane-1,3-dione and trifluoromethyl-1H-pyrazole analogues

Abstract

A series of 2-(arylidene)-1-(4-chlorophenyl)-4,4,4-trifluorobutane-1,3-diones (2–4), 4-(arylidene)-3-(4-chlorophenyl)-5-(trifluoromethyl)-4H-pyrazoles (5–7), 1-(4-chlorophenyl)-4,4,4-trifluoro-2-(2-(aryl)hydrazono)butane-1,3-diones (8, 9), 3-(4-chlorophenyl)-4-(2-(aryl)hydrazono)-5-(trifluoromethyl)-4H-pyrazoles (10, 11), 2-((3-(4-chlorophenyl)-1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)methylene)malononitrile (13), 2-((5-(4-chlorophenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methylene)cycloalkan-1-ones (14, 15) and 1-(aryl)-3-(5-(4-chlorophenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)prop-2-en-1-ones (16, 17) were designed, synthesized and evaluated for their in vitro antitumor activity. 1-(4-Chlorophenyl)-4,4,4-trifluoro-2-(2-(4-methoxyphenyl)hydrazono)butane-1,3-dione (8) showed potential and broad spectrum antitumor activity compared to the known drug 5-FU with GI₅₀, (6.61 and 22.60 µM), TGI (42.66 and <100?µM) and LC₅₀ (93.33 and <100?µM) values, respectively. On the other hand, compound 8 yielded selective activities toward melanoma, colon, non-small lung and breast cancer cell lines compared with erlotinib and gefitinib. Molecular docking methodology was performed for compound 8 into binding site of B-RAFV600E and EGFR kinases which showed similar binding mode to vemurafenib (PLX4032) and erlotinib, respectively.     

Benzo[g]quinazolin-based scaffold derivatives as dual EGFR/HER2 inhibitors

Targeting EGFR has proven to be beneficial in the treatment of several types of solid tumours. So, a series of novel 2-(4-oxo-3-(4-sulfamoylphenyl)-3,4-dihydrobenzo[g]quinazolin-2-ylthio)-N-substituted acetamide 5–19 were synthesised from the starting material 4-(2-mercapto-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 4, to be evaluated as dual EGFR/HER2 inhibitors. The target compounds 5–19, were screened for their cytotoxic activity against A549 lung cancer cell line. The percentage inhibition of EGFR enzyme was measured and compared with erlotinib as the reference drug. Compounds 6, 8, 10, and 16 showed excellent EGFR inhibitory activity and were further selected for screening as dual EGFR/HER2 inhibitors. The four selected compounds showed IC₅₀ ranging from 0.009 to 0.026?µM for EGFR and 0.021 to 0.069?µM for the HER2 enzyme. Compound 8 was found to be the most potent in this study with IC₅₀ 0.009 and 0.021?µM for EGFR and HER2, respectively.     

Compounds with neuroprotective activity from the medicinal plant Machilus thunbergii

The dichloromethane fraction of the bark of Machilus thunbergii Sieb. et Zucc. (Lauraceae) significantly protected primary cultures of rat cortical cells exposed to the excitotoxic amino acid, L-glutamate. Through the activity-guided isolation from the CH₂Cl₂ fraction, (+)-9′-hydroxygalbelgin (1), isogalcatin B (2), (7S,8S,8′R)-3′,4′-dimethoxy-3,4,-methylenedioxylignan-7-ol (3), 1-hydroxy-7-hydroxymethyl-6-methoxyxanthone (4), 5,7-dimethoxy-3′,4′-methylenedioxyflavan-3-ol (5), (+)-(3S,4S,6R)-3,6-dihydroxypiperitone (6), protocatechuic acid methyl ester (7) and tyrosol (8) were obtained. All of them had significant neuroprotective activities against glutamate-induced neurotoxicity in primary cultures of rat cortical cells at concentrations ranging from 0.1 μM to 10.0 μM and were comparable to MK-801, a well-known inhibitor of glutamate receptor.     

Chemical Constituents of Cape Aloe and Their Synergistic Growth-Inhibiting Effect on Ehrlich Ascites Tumor Cells

The constituents of cape aloe were investigated after a preliminary screening of the growth-inhibiting effect on Ehrlich ascites tumor cells (EATC) of several extracts of this plant. Ten compounds were isolated from the dichloromethane (CH₂Cl₂) extract that showed the strongest activity, and their structures were elucidated as aloe-emodin (1), p-hydroxybenzaldehyde (2), p-hydroxyacetophenone (3), pyrocatechol (4), 10-oxooctadecanoic acid (5), 10-hydroxyoctadecanoic acid (6), methyl 10-hydroxyoctadecanoate (7), 7-hydroxy-2,5-dimethylchromone (8), furoaloesone (9), and 2-acetonyl-8-(2-furoylmethyl)-7-hydroxy-5-methylchromone (10) based on MS and various NMR spectroscopic techniques. Compounds 2–7 were isolated for the first time from cape aloe. Compounds 4–7 and 10 showed a significant growth-inhibiting effect, and compound 1 exhibited a remarkable synergistic effect on compounds 8–10, which was not observed with the treatment by each compound alone on EATC. These results suggest that the strong growth-inhibiting effect of the CH₂Cl₂ extract was dependent not on one compound alone, but on the synergistic effect from the combination of compound 1 and the other compounds.     

Synthesis of new pyridothienopyrimidinone derivatives as Pim-1 inhibitors

Four series of pyridothienopyrimidin-4-one derivatives were designed and prepared to improve the pim-1 inhibitory activity of the previously reported thieno[2,3-b]pyridines. Significant improvement in the pim-1 inhibition and cytotoxic activity was achieved using structure rigidification strategy via ring closure. Six compounds (6c, 7a, 7c, 7d, 8b and 9) showed highly potent pim-1 inhibitory activity with IC₅₀ of 4.62, 1.18, 1.38, 1.97, 8.83 and 4.18?μM, respectively. Four other compounds (6b, 6d, 7b and 8a) showed moderate pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on three cell lines [MCF7, HCT116 and PC3]. Compounds 7a [the 2-(2-chlorophenyl)-2,3-dihydro derivative] and 7d [the 2-(2-(trifluoromethyl)-phenyl)-2,3-dihydro derivative] displayed the most potent cytotoxic effect on the three cell lines tested consistent with their highest estimated pim-1 IC₅₀ values.     

Synthesis of new N,N′-bis[1-aryl-3-(piperidine-1-yl)propylidene]hydrazine dihydrochlorides and evaluation of their cytotoxicity against human hepatoma and breast cancer cells

Abstract

N,N′-Bis[1-aryl-3-(piperidine-1-yl)propylidene]hydrazine dihydrochlorides were synthesized by the reaction of 2 mols of 1-aryl-3-(piperidine-1-yl)-1-propanone hydrochlorides with 1?mol of hydrazine hydrate. Aryl part was C₆H₅ (P1), 4-CH₃C₆H₄ (P2), 4-CH₃OC₆H₄ (P3), 4-HOC₆H₄ (P4), 4-ClC₆H₄ (P5), 3-CH₃OC₆H₄ (P6), 4-FC₆H₄ (P7) and 4-BrC₆H₄ (P8). Except P1, all compounds were reported for the first time. The chemical structures were confirmed by UV, ¹H NMR, ¹³C NMR and HRMS spectra. P1, P2, P7 and P8 against human hepatoma (Huh7) cells and P1, P2, P4, P5, P6, P7 and P8 against breast cancer (T47D) cells have shown cytotoxicity. P1, P2 and P7 had more potent cytotoxicity against Huh7 cells than the reference compound 5-FU, whereas only P2 was more potent than the 5-FU against T47D cells. Representative compound P7 inhibited the mitochondrial respiration at 144, 264 and 424?µM concentrations dose-dependantly in liver homogenates. The results suggest that P1, P2, P7 and P8 may serve as model compounds for further synthetic studies.     

A 2′←5′-Adenylate Trimer With a Positively Charged 2′(3′)-Terminal 8-(4-Aminobunl)Aminoadenosine Residue: Synthesis,Conformation and RNase L Binding

Abstract

An analogue of the 2-5A core trimer containing an 8-(4-aminobutyl)-aminoadenosine (1; A) residue at the 2′(3′)-terminus [2; (2′,5′)A₂A^?] was synthesized. The conformation of (2′,5′)A₂A^? was studied by ₁H, ¹³C-NMR, and CD spectroscopy. The (2′,5′)A₂A^? exhibits very low binding ability to the RNase L of mouse L cells, but slightly enhanced resistance to digestion by SVPD compared to the parent trimer.     

Synthesis and biological evaluation of tricarbonyl Re(I) and Tc(I) complexes anchored by poly(azolyl)borates: application on the design of radiopharmaceuticals for the targeting of 5-HT<Subscript>1A</Subscript> receptors

The building blocks fac-[^99mTc{κ³-HB(tim^Me)₃}(CO)₃] and fac-[^99mTc{κ³-R(μ-H)B(tim^Me)₂}(CO)₃] [R is H (4a), Ph (5a); tim^Me is 2-mercapto-1-methylimidazolyl] were obtained almost quantitatively by reacting fac-[^99mTc(CO)₃(H₂O)₃]⁺ with the corresponding scorpionate. These compounds cross the intact blood–brain barrier in mice, with significant retention in the case of 4a and 5a. Using 4a as the lead structure, we have synthesized the functionalized complexes fac-[M{κ³-H(μ-H)B(tim^Bu-pip)₂}(CO)₃] [M is Re (8), ^99mTc (8a); tim^Bu-pip is methyl[4-((2-methoxyphenyl)-1-piperazinyl)butyl](2-mercapto-1-methylimidazol-5-yl)methanamide] and fac-[M{κ ³-H(μ-H)B(tim^Me)(tim^Bu-pip)}(CO)₃] [M is Re (9), ^99mTc (9a)] and evaluated their potential as radioactive probes for the targeting of brain 5-HT_1A serotonergic receptors. The Re complexes exhibit excellent affinity [IC₅₀=0.172 ± 0.003 nM (8); IC₅₀=0.65 ± 0.01 nM (9)] for the 5-HT_1A receptor. The radioactive congeners (^99mTc) have shown an initial brain uptake of 1.38 ± 0.46%ID g⁻¹ (8a) and 0.43 ± 0.12%ID g⁻¹ (9a), but suffer from a relatively fast washout.