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Abstract: Conantokin‐G (con‐G) is a small, γ‐carboxyglutamic acid (Gla)‐containing peptide that functions neurophysiologically by inhibiting the N‐methyl‐d ‐aspartate receptor (NMDAR). In the current study, the receptor binding properties of an alanine‐rich, Gla‐deficient con‐G variant, Ala‐con‐G, were assessed following tracer radioiodination with 125I. Direct binding experiments with [125I]Ala‐con‐G yielded a single site defined by a Kd value of 516 ± 120 nm . Displacement of [125I]Ala‐con‐G binding by Ala‐con‐G resulted in 100% displacement with an IC50 value of 564 ± 33 nm , while heterologous displacement by con‐G[S16Y], con‐G, con‐T, and con‐R[1–17] yielded IC50 values in the range of 15–45 μm . No displacement was observed with d ‐γ‐con‐G or con‐G[L5A], analogs that are inactive at NMDARs. Specific [125I]Ala‐con‐G binding was displaced by NMDA and 2‐amino‐5‐phosphopentanoic acid in a dose‐dependent manner, suggesting an interaction at the glutamate binding site. The direct binding of [125I]Ala‐con‐G to adult rat brain sections revealed an anatomical distribution of binding sites in all regions known to contain the NR2B subunit of the NMDAR. These results constitute the only known demonstration of the direct binding of a radiolabeled conantokin to the NMDARs present in rat brain membrane preparations and rat brain sections, and suggest that radiolabeled Ala‐con‐G, and similar conantokin derivatives, may find utility as probes of NMDARs in a variety of systems. 相似文献
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Molecular recognition of a carboxy pyridostatin toward G‐quadruplex structures: Why does it prefer RNA?
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Roberta Rocca Carmine Talarico Federica Moraca Giosuè Costa Isabella Romeo Francesco Ortuso Stefano Alcaro Anna Artese 《Chemical biology & drug design》2017,90(5):919-925
The pyridostatin (PDS) represents the lead compound of a family of G‐quadruplex (G4) stabilizing synthetic small molecules based on a N,N′‐bis(quinolinyl)pyridine‐2,6‐dicarboxamide scaffold. Its mechanism of action involves the induction of telomere dysfunction by competing for binding with telomere‐associated proteins, such as human POT1. Recently, through a template‐directed “in situ” click chemistry approach, a PDS derivative, the carboxypyridostatin (cPDS), was discovered. It has the peculiarity to exhibit high molecular specificity for RNA over DNA G4, while PDS is a good generic RNA and DNA G4‐interacting small molecule. Structural data on the binding modes of these compounds are not available, and the selectivity mode of cPDS toward TERRA G4 is unknown too. Therefore, this work is aimed at rationalizing the selectivity of cPDS versus TERRA G4 by means of molecular dynamics and docking simulations, coupled to better understand the binding mode of these compounds to telomeric G4 structures. The comprehensive analysis of cPDS binding mode and its conformational behavior demonstrates the importance of the ligand conformation properties coupled with a remarkable solvation contribution. This work is expected to provide valuable clues for further rational design of novel and selective TERRA G4 binders. 相似文献
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Abstract: Cadherins are a family of calcium‐dependent cell‐surface proteins that are fundamental in controlling the development and maintenance of tissues. Motif B of E‐cadherin seems to be a crucial calcium‐binding site as single point mutations (D134A and D134K) completely inactivate its adhesion activity. We analyzed peptide models corresponding to motif B (amino acids 128–144) as well as selected mutations of this motif. Our NMR studies showed that this motif B sequence is actually an active calcium‐binding region, even in the absence of the rest of the cadherin molecule. We found that the binding affinity of this motif is very sensitive to mutations. For example, our peptide P128‐144 with the native calcium‐binding sequence has an affinity of Kd 0.4 mm , whereas the mutants P128‐144/D134A and P128‐144/D134K containing the replacement of Asp134 by Ala and Lys, have Kd values of only 1.5 and 11 mm , respectively. Removing Asp at position 134, which correlates with the loss of adhesion activity, decreases calcium‐binding affinity 20‐fold. Ala132, along with residues Asp134, Asp136 and Asn143, is involved in calcium binding in solution. We also demonstrated that the calcium‐binding affinity can be increased ≈ 3‐fold when an additional Asp is introduced at position 132. In 50% organic solvent, this binding affinity of peptide P128‐144/A132D (17‐mer) from E‐cadherin is similar to that of peptide P72–100/C73–77–91A (29‐mer) from α‐lactalbumin. 相似文献
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Swati S. Chitnis Chellasamy Selvaakumar Dhanashree D. Jagtap Ravi P. Barnwal Kandala V. R. Chary Smita D. Mahale Tarala D. Nandedkar 《Chemical biology & drug design》2009,73(6):637-643
Follicle‐stimulating hormone (FSH) receptor binding inhibitor (FRBI‐8) is a novel octapeptide purified from human ovarian follicular fluid. In vitro, it inhibits the binding of FSH to granulosa cells and in vivo, it induces atresia in developing follicles in rodents. This peptide, when administered to marmosets and bonnet monkeys, altered the circulating progesterone levels. This study was carried out to elucidate structure of the FRBI‐8 and understand its mechanism of inhibiting interaction of FSH to its receptors. Homology modeling predicted that the FRBI‐8 adopts a turn and random coil. This is further confirmed by circular dichroism and NMR. Docking studies of the FRBI‐8 with reported FSH–FSHR hormone binding (FSHRHB) domain complex using zdock algorithm revealed that the FRBI‐8 binds to FSHβL2–FSHRHB binding interface which is otherwise known to be crucial for activation of signal transduction cascade. FRBI‐8 analogs were designed by replacing the acidic amino acid residues at positions 2, 5 and 6 with Ala, individually. Docking studies revealed that D6A mutant (FRBI‐8D6A) had a higher binding affinity than the native FRBI‐8. In vitro radioreceptor assay with FRBI‐8D6A showed 50% lower IC50 compared with the FRBI‐8, confirming the in silico observations. Thus, the study reveals that both FRBI‐8 and FRBI‐8D6A interfered with the binding of FSH to its receptor. 相似文献
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S. Claudel O. Tasseau S. Sagan C. Grison P. Coutrot S. Lavielle 《Chemical biology & drug design》2004,64(5):186-193
Abstract: Glycine‐9 and leucine‐10 of substance P (SP) are critical for (NK)‐1 receptor recognition and agonist activity. Proψ(Z)‐CH=CH(CH3)‐CONH)Leu (or Met) and Proψ((E)‐CH=CH(CH3)‐CONH)Leu (or Met) have been introduced in the sequence of SP, in order to restrict the conformational flexibility of the C‐terminal tripeptide, Gly‐Leu‐Met‐NH2, of SP. Proψ((Z)‐CH=C(CH2CH(CH3)2)‐CONH)Met‐NH2, with an isobutyl substituent to mimic the Leu side‐chain, was also incorporated in place of the C‐terminal tripeptide. The substituted‐SP analogs were tested for their affinity to human NK‐1 receptor specific binding sites (NK‐1M and NK‐1m) and their potency to stimulate adenylate cyclase and phospholipase C in Chinese Hamster ovary (CHO) cells transfected with the human NK‐1 receptor. The most potent SP analogs [Pro9ψ((Z)CH=C(CH3)CONH)Leu10]SP and [Pro9ψ ((E)CH=C(CH3)CONH)Leu10]SP, are about 100‐fold less potent than SP on both binding sites and second messenger pathways. These vinylogous (Z)‐ or (E)‐CH=C(CH3)‐ or (Z)‐CH=C(CH2CH(CH3)2) moieties hamper the correct positioning of the C‐terminal tripeptide of SP within both the NK‐1M‐ and NK‐1m‐specific binding sites. The origin of these lower potencies is related either to an incorrect peptidic backbone conformation and/or an unfavorable receptor interaction of the methyl or isobutyl group. 相似文献
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Jillian R. Hufgard Jenna L.N. Sprowles Emily M. Pitzer Sheryl E. Koch Min Jiang Qin Wang Xiang Zhang Jacek Biesiada Jack Rubinstein Alvaro Puga Michael T. Williams Charles V. Vorhees 《Journal of applied toxicology : JAT》2019,39(4):603-621
Polychlorinated biphenyls (PCBs) are toxic environmental pollutants. Humans are exposed to PCB mixtures via contaminated food or water. PCB exposure causes adverse effects in adults and after exposure in utero. PCB toxicity depends on the congener mixture and CYP1A2 gene activity. For coplanar PCBs, toxicity depends on ligand affinity for the aryl hydrocarbon receptor (AHR). Previously, we found that perinatal exposure of mice to a three‐coplanar/five‐noncoplanar PCB mixture induced deficits in novel object recognition and trial failures in the Morris water maze in Cyp1a2?/?::Ahrb1 C57BL6/J mice compared with wild‐type mice (Ahrb1 = high AHR affinity). Here we exposed gravid Cyp1a2?/?::Ahrb1 mice to a PCB mixture on embryonic day 10.5 by gavage and examined the F1 and F3 offspring (not F2). PCB‐exposed F1 mice exhibited increased open‐field central time, reduced acoustic startle, greater conditioned contextual freezing and reduced CA1 hippocampal long‐term potentiation with no change in spatial learning or memory. F1 mice also had inhibited growth, decreased heart rate and cardiac output, and impaired fertility. F3 mice showed few effects. Gene expression changes were primarily in F1 PCB males compared with wild‐type males. There were minimal RNA and DNA methylation changes in the hippocampus from F1 to F3 with no clear relevance to the functional effects. F0 PCB exposure during a period of rapid DNA de‐/remethylation in a susceptible genotype produced clear F1 effects with little evidence of transgenerational effects in the F3 generation. While PCBs show clear developmental neurotoxicity, their effects do not persist across generations for effects assessed herein. 相似文献
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L.O. Sillerud E.J. Burks W.M. Brown D.C. Brown R.S. Larson 《Chemical biology & drug design》2004,64(4):127-140
Abstract: We have previously described a disulfide‐linked cyclic nonapeptide (inhibitory peptide‐01, IP01), with the sequence CLLRMRSIC, which binds to intercellular adhesion molecule‐1 (ICAM‐1), and blocks binding to its counter‐structure, the integrin αLβ2 (leukocyte functional antigen‐1, LFA‐1) (Sillerud et al., J. Peptide Res. 62, 2003: 97). We now report the optimization of this peptide by means of single homologous amino acid substitutions to yield a new peptide (IP02‐K6; CLLRMKSAC) which shows an approximately sixfold improvement in inhibitory activity of multivalent leukocyte binding (inhibition constant for 50% inhibition, IC50 = 90 μm ) compared with IP01 (IC50 = 580 μm ). This improvement in activity gives IP02‐K6 potent in vivo activity in a murine model of ischemia reperfusion injury (Merchant et al., Am. J. Physiol. Heart Circ. 284, 2003: H1260). In order to determine the structural features relevant to ICAM‐1‐binding, we have determined the structure of IP02‐K6 using proton nuclear magnetic resonance (NMR) spectroscopy and restrained molecular modeling. In our previously reported study of solution models of IP01, we observed three interconverting conformations during low‐temperature molecular dynamics simulation. In the present study, we find a single conformation of IP02‐K6 similar to one of the previously found conformations of IP01 (family C). In particular, an R4‐S7 β‐turn is present in similar proportions in both conformation C of IP01 and in IP02‐K6; this motif is important in binding to ICAM‐1 because this turn enables the IP02‐K6 backbone to drape over proline‐36 on ICAM‐1. The NMR‐derived solution model of IP02‐K6 was found to dock at the αLβ2‐binding site on ICAM‐1 with no changes in peptide backbone conformation. This docking model displaced five of the 15 αLβ2 residues at the ICAM‐1‐binding site and provided a rationale for understanding the quantitative relationship between IP02‐K6 structure and biologic activity. 相似文献
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P. Fu S. Layfield T. Ferraro H. Tomiyama J. Hutson L. Otvos G.W. Tregear R.A.D. Bathgate J.D. Wade 《Chemical biology & drug design》2004,63(2):91-98
Abstract: Biotin‐avidin immobilization has been routinely used as a tool to study peptide–receptor and peptide–antibody interactions. Biotinylated peptides can also be employed to localize cells that express the peptides’ receptor, and to analyse ligand‐receptor binding. Insulin‐like peptide 3 (INSL3) is a peptide hormone which contains A‐ and B‐chains connected by two disulphide bonds and plays a role in testicular descent during sexual development. In order to study the interaction of INSL3 with its receptor LGR8, a G protein‐coupled receptor, we chemically synthesized Nα‐mono‐biotinylated human INSL3 (B‐hINSL3) and compared it structurally and biologically with hINSL3. Both peptides exhibited similar, but high, receptor binding affinities on human foetal kidney fibroblast 293T cells transfected human LGR8 based on a competition radioreceptor assay with 33P‐labelled relaxin H2 (B33). The modified B‐hINSL3 showed full biological activity as determined by the stimulation of gubernacular cell proliferation. The labelled B‐hINSL3 contains a higher α‐helix content, and this increased helical structure is accompanied by an increase in ability to stimulate cAMP accumulation in 293T cells expressing LGR8. Our results suggest that the N‐terminal region of the A‐chain is not involved in the interaction of INSL3 with its receptor. However, the introduction of biotin onto the N‐terminus of the A‐chain promoted conformational stability which, in turn, permitted better receptor activation. 相似文献
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The Truncated Human Telomeric Sequence forms a Hybrid‐Type Intramolecular Mixed Parallel/antiparallel G‐quadruplex Structure in K+ Solution
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In 80–90% tumor cells, telomerase becomes active and stabilizes the length of telomeres. The formation and stabilization of G‐quadruplexes formed from human telomeric sequences have been proved able to inhibit the activity of telomerase, thus human telomeric G‐quadruplex structure has become a potential target for the development of cancer therapy. Hence, structure of G‐quadruplex formed in K+ solution has been an attractive hotspot for further studies. However, the exact structure of human telomeric G‐quadruplex in K+ is extremely controversial, this study provides information for the understanding of different G‐quadruplexes. Here, we report that 22nt and 24nt human telomeric sequences form unimolecular hybrid‐type mixed parallel/antiparallel G‐quadruplex in K+ solution elucidated utilizing Circular Dichroism, Differential Scanning Calorimetry, and gel electrophoresis. Moreover, individual configuration of these two sequences was speculated in this study. The detailed structure information of the G‐quadruplex formed under physiologically relevant condition is necessary for structure‐based rational drug design. 相似文献
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《Journal of labelled compounds & radiopharmaceuticals》2017,60(9):431-438
Targeted delivery of chemotherapeutic drug at the tumor site enhances the efficacy with minimum systemic exposure. Towards this, drugs conjugated with peptides having affinity towards a particular molecular target are recognized as affective agents for targeted chemotherapy. Thus, in the present study, tumor‐homing asparagine‐glycine‐arginine (NGR) peptide ligand was conjugated to DNA alkylating nitrogen mustard, chlorambucil (CLB). The peptide‐drug conjugate (PDC), CLB‐c(NGR), was radiolabeled with 99mTc‐HYNIC core to trace its pharmacokinetics and biodistribution pattern. In vitro cell‐binding studies of 99mTc‐HYNIC‐CLB‐c(NGR) were conducted in murine melanoma B16F10 cells. The cytotoxicity studies conducted by incubation of the peptide/drug/PDC with B16F10 cells demonstrated enhanced cytotoxic effect of PDC in comparison to either the peptide or the drug alone. In vivo biodistribution studies in C57BL6 mice bearing melanoma tumor showed maximum tumor uptake at 30 minutes pi (2.45 ± 0.28% ID/g), which reduced to 0.77 ± 0.1% ID /g at 3 hours pi. The radiotracer being hydrophilic cleared rapidly from the heart, lungs, liver, and muscle. The tumor‐to‐blood and tumor‐to‐muscle ratios improved with time. This study opens avenues for conjugation of other targeting peptides with the drug CLB for enhanced toxicity at the diseased site. 相似文献
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Solid‐phase organic synthesis of chiral,non‐racemic 1,2,4‐trisubstituted 1,4‐diazepanes with high σ1 receptor affinity
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The aim of this work was to transfer the established chiral‐pool synthesis of 1,2,4‐trisubstituted 1,4‐diazepanes in solution on the solid phase. For this purpose, (S)‐configured amino acids, (S)‐alanine, and (S)‐leucine, with a small methyl and a larger isobutyl moiety were attached to the solid support 9 by reductive amination. After five reaction steps on the solid support, the 1,4‐diazepanes (S)‐ 19a , b were cleaved off and reductively alkylated to afford the 1,2,4‐trisubstituted 1,4‐diazepanes (S)‐ 20a and (S)‐ 21b , respectively. Both compounds show high σ1 affinity and selectivity over the σ2 subtype. 相似文献
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Alice Borghini Daniele Pietra Michele Leonardi Irene Giorgi Anna M. Bianucci 《Chemical biology & drug design》2013,82(1):22-38
A series of N‐[9‐(ortho‐fluorobenzyl)‐2‐phenyl‐8‐azapurin‐6‐yl]‐amides were synthesized and tested for their affinity toward A1, A2A, and A3 adenosine receptor subtypes. Biological results demonstrated that the introduction of a fluorine atom at the ortho position of the 9‐benzyl group generally enhanced affinity toward A1 subtype and did not significantly affect A2A and A3 affinity. Very interesting is the compound bearing a meta‐fluorophenyl substituent on the carbonyl carbon of the amide group, which shows significantly high A1/A2A‐A3 selectivity. Compounds of this new series, together with the previously published analogs without the fluorine atom on the 9‐benzyl group, constituted the starting dataset for the development of QSAR models. The models obtained were able to rationally describe the affinity trends resulting from biological testing and to enable investigation of the role of different substituents on the 8‐azapurine scaffold, as well as the influence of the newly introduced fluorine atom on the benzyl moiety. The said QSAR models can also assist in the design of new compounds selectively active on A1 adenosine receptors. Furthermore, a molecular docking study was carried out to assess hypothetical binding mode of N‐[9‐(ortho‐fluorobenzyl)‐2‐phenyl‐8‐azapurin‐6‐yl]‐amides to A1 adenosine receptors. 相似文献
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Computer‐aided drug design of small molecule inhibitors of the ERCC1‐XPF protein–protein interaction
Francesco Gentile Ahmed H. Elmenoufy Gloria Ciniero David Jay Feridoun Karimi‐Busheri Khaled H. Barakat Michael Weinfeld Frederick G. West Jack A. Tuszynski 《Chemical biology & drug design》2020,95(4):460-471
The heterodimer of DNA excision repair protein ERCC‐1 and DNA repair endonuclease XPF (ERCC1‐XPF) is a 5′–3′ structure‐specific endonuclease essential for the nucleotide excision repair (NER) pathway, and it is also involved in other DNA repair pathways. In cancer cells, ERCC1‐XPF plays a central role in repairing DNA damage induced by chemotherapeutics including platinum‐based and cross‐linking agents; thus, its inhibition is a promising strategy to enhance the effect of these therapies. In this study, we rationally modified the structure of F06, a small molecule inhibitor of the ERCC1‐XPF interaction (Molecular Pharmacology, 84 , 2013 and 12), to improve its binding to the target. We followed a multi‐step computational approach to investigate potential modification sites of F06, rationally design and rank a library of analogues, and identify candidates for chemical synthesis and in vitro testing. Our top compound, B5 , showed an improved half‐maximum inhibitory concentration (IC50) value of 0.49 µM for the inhibition of ERCC1‐XPF endonuclease activit, and lays the foundation for further testing and optimization. Also, the computational approach reported here can be used to develop DNA repair inhibitors targeting the ERCC1‐XPF complex. 相似文献
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Vattoly J. Majo Ramin V. Parsey Jaya Prabhakaran J. John Mann J. S. Dileep Kumar 《Journal of labelled compounds & radiopharmaceuticals》2008,51(3):132-136
4‐[3‐[4‐(2‐Methoxyphenyl)piperazin‐1‐yl]propoxy]‐4‐aza‐tricyclo[5.2.1.02,6]dec‐8‐ene‐3,5‐dione (4), a potent and selective 5‐HT1A agonist, was labeled by 11C‐methylation of the corresponding desmethyl analogue 3 with 11C‐methyl triflate. The precursor molecule 3 was synthesized from commercially available endo‐N‐hydroxy‐5‐norbornene‐2,3‐dicarboximide in two steps with an overall yield of 40%. Radiosynthesis of 11C‐4 was achieved in 35 min in 20±5% yield (n=6) at the end of synthesis with a specific activity of 2600±250 Ci/mmol. In vivo positron emission tomography (PET) studies in baboon revealed rapid uptake of the tracer into the brain. However, lack of specific binding indicates that 11C‐4 is not useful as a 5‐HT1A agonist PET ligand for clinical studies. Copyright © 2008 John Wiley & Sons, Ltd. 相似文献
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《Journal of labelled compounds & radiopharmaceuticals》2002,45(1):1-11
Peptide nucleic acids (PNAs) are a unique class of synthetic macromolecules, originally designed as ligands for the recognition of double stranded DNA. From a chemical point of view, the deoxyribose phosphate backbone of DNA is replaced by a pseudo‐peptide N‐(2‐aminoethyl)glycyl backbone, while the nucleobases of DNA (adenine, guanine, cytosine and thymine) are retained. Due to the increasing interest in the labeling of peptide nucleic acids (PNAs) as potent diagnostic agents in nuclear medicine, we have used and adapted the reliable methodology developed for the fluorine‐18 labeling of oligonucleotides and have now demonstrated that it is possible to label PNAs in sufficient quantity and with high specific radioactivity for PET studies in a time compatible with the half life of fluorine‐18. Copyright © 2002 John Wiley & Sons, Ltd. 相似文献
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Pengli Zhang Chengping Li Xiaoyue Ji Mingjie Gao Sifan Lyu Xiaojun Dai Jiangfeng Du 《Chemical biology & drug design》2020,95(3):332-342
Programmed death 1 (PD‐1) is a key immune checkpoint molecule. When it binds to programmed death‐ligand 1 (PD‐L1), it can negatively regulate the immune response. Therefore, blockade of the PD‐1/PD‐L1 interaction could unleash the power of immune system. Though successes achieved by anti‐PD‐1/PD‐L1 antibody drugs in clinical for various cancers, many intrinsic limitations of the high molecular weight drugs require alternatives such as peptide drugs and chemical compounds. In this study, we described a novel in silico approach which was used to screen peptides from PDB database and aimed to identify peptides that have potential to bind the PD‐L1 binding area of PD‐1 molecule. Based on the docking poses, eight peptides were synthesized and measured for their binding abilities by surface plasma resonance technique. The KD values of the synthesized peptides ranged from 10.0 to 133.0 μM. Furthermore, the binding mechanism between PD‐1 and the peptides was studied. In conclusion, we established a fast and reliable screening method for peptide discovery, which could be applied for identifying peptide inhibitors of various targets. The synthesized peptides could be served as starting points for designing PD‐1 drug for cancer immunotherapy. 相似文献
19.
《Journal of labelled compounds & radiopharmaceuticals》2006,49(6):489-504
2‐exo‐(2′‐Fluoro‐3′‐(4‐fluorophenyl)‐pyridin‐5′‐yl)‐7‐azabicyclo[2.2.1]heptane (F2PhEP), a novel, epibatidine‐based, α4β2‐selective nicotinic acetylcholine receptor antagonist of low toxicity, as well as the corresponding N‐Boc‐protected chloro‐ and bromo derivatives as precursors for labelling with fluorine‐18 were synthesized from 7‐tert‐butoxycarbonyl‐7‐azabicyclo[2.2.1]hept‐2‐ene in 13, 19 and 8% overall yield, respectively. [18F]F2PhEP was prepared in 8–9% overall yield (non‐decay‐corrected) using 1 mg of the bromo derivative in the following two‐step radiochemical process: (1) no‐carrier‐added nucleophilic heteroaromatic ortho‐radiofluorination with the activated K[18F]F‐Kryptofix®222 complex in DMSO using microwave activation at 250 W for 90 s, followed by (2) quantitative TFA‐induced removal of the N‐Boc protective group. Radiochemically pure (>95%) [18F]F2PhEP (1.48–1.66 GBq, 74–148 GBq/µmol) was obtained after semi‐preparative HPLC (Symmetry® C18, eluent aqueous 0.05 M NaH2PO4 CH3CN: 78/22 (v:v)) in 75–80 min starting from an 18.5 GBq aliquot of a cyclotron‐produced [18F]fluoride production batch. Copyright © 2006 John Wiley & Sons, Ltd. 相似文献
20.
Synthesis and evaluation of a 18F‐labeled 4‐phenylpiperidine‐4‐carbonitrile radioligand for σ1 receptor imaging
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Jiajun Ye Xia Wang Winnie Deuther‐Conrad Jinming Zhang Jianzhou Li Xiaojun Zhang Liang Wang Jörg Steinbach Peter Brust Hongmei Jia 《Journal of labelled compounds & radiopharmaceuticals》2016,59(9):332-339
We report the design and synthesis of several 4‐phenylpiperidine‐4‐carbonitrile derivatives as σ1 receptor ligands. In vitro radioligand competition binding assays showed that all the ligands exhibited low nanomolar affinity for σ1 receptors (Ki(σ1) = 1.22–2.14 nM) and extremely high subtype selectivity (Ki(σ2) = 830–1710 nM; Ki(σ2)/Ki(σ1) = 680–887). [18F]9 was prepared in 42–46% isolated radiochemical yield, with a radiochemical purity of >99% by HPLC analysis after purification, via nucleophilic 18F‐ substitution of the corresponding tosylate precursor. Biodistribution studies in mice demonstrated high initial brain uptakes and high brain‐to‐blood ratios. Administration of SA4503 or haloperidol 5 min prior to injection of [18F]9 significantly reduced the accumulation of radiotracers in organs known to contain σ1 receptors. Two radioactive metabolites were observed in the brain at 30 min after radiotracer injection. [18F]9 may serve as a lead compound to develop suitable radiotracers for σ1 receptor imaging with positron emission tomography. 相似文献