Structure−Activity Relationships in Carboxamide Derivatives Based on the Targeted Delivery of Radionuclides and Boron Atoms by Means of Peripheral Benzodiazepine Receptor Ligands

Cappelli, Andrea; Mohr, Gal.la Pericot; Gallelli, Andrea; Giuliani, Germano; Anzini, Maurizio; Vomero, Salvatore; Fresta, Massimo; Porcu, Patrizia; Maciocco, Elisabetta; Concas, Alessandra; Biggio, Giovanni; Donati, Alessandro

doi:10.1021/jm034068b

Cited by 38 publications

(28 citation statements)

References 20 publications

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“…Encouraged by these results, further studies among the quinolinecarboxamide derivatives were performed with the aim to optimize the interaction with TSPO and once again develop candidates for PET studies [68]. A novel series of quinoline compounds was synthesized in which the benzyl substituent of compound (60) was replaced with a 1,2-dicarba-closo-dedecaboran-1-yl-methyl moiety, Table 6, in order to obtain a TSPO ligand liable to be labeled with different radionuclides and potentially useful in boron neutron capture therapy (BNCT) [102].…”

Section: Isoquinolinecarboxamide Derivativesmentioning

confidence: 99%

“…(1) [1,65,66], a number of structurally different classes of ligands have been reported, including the isoquinolinecarboxamides [67][68][69], of which PK 11195 (3), Fig (1) [58] is currently regarded as the standard TSPO ligand, benzothiazepines [70][71][72], benzoxazepines [73,74], phenoxyphenylacetamides [75,76], imidazopyridineacetamides [77][78][79][80], indoleacetamides [81,82], indol-3-ylglyoxylamides [56, 57, 83, 84,] and pyrazolopyrimidineacetamides [85,86]. Kassiou and colleagues have recently reviewed these major classes of TSPO ligands [24].…”

Section: Introductionmentioning

confidence: 99%

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Structural Requirements to Obtain Highly Potent and Selective 18 kDa Translocator Protein (TSPO) Ligands

Taliani

Pugliesi²,

Settimo

2011

CTMC

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The (18 kDa) Translocator Protein (TSPO), was initially identified in 1977 as peripheral binding site for the benzodiazepine diazepam and named "Peripheral-type benzodiazepine receptor (PBR)". It is an evolutionarily well-conserved protein particularly located at the outer/inner mitochondrial membrane contact sites, in closely association with the 32 kDa voltage-dependent anion channel (VDAC) and the 30 kDa adenine nucleotide translocase (ANT), thus forming the mitochondrial permeability transition pore (MPTP). TSPO is ubiquitary expressed in peripheral tissues (steroid producing tissues, liver, heart, kidney, lung, immune system) and in lower levels in the central nervous system, where it is mainly located in glial cells, and in neurons. TSPO is involved in a variety of biological processes such as cholesterol transport, steroidogenesis, calcium homeostasis, lipid metabolism, mitochondrial oxidation, cell growth and differentiation, apoptosis induction, and regulation of immune functions. In the last decade, many studies have reported that TSPO basal expression is altered in a number of human pathologies, such as cancer and neurodegenerative disorders (Huntington's and Alzheimer's diseases), as well as in various forms of brain injury and inflammation and anxiety. Consequently, TSPO has not only been suggested as a promising drug target for a number of therapeutic applications (anticonvulsant, anxiolytic, immunomodulating, etc.), but also as valid diagnostic marker for related-disease state and progression, prompting the development of specific labelled ligands as powerful tools for imaging techniques. A number of structurally different classes of ligands have been reported, showing high affinity and selectivity towards TSPO. Indeed, most of these ligands have been designed starting from selective CBR ligands which were structurally modified in order to shift their affinity towards TSPO. Extensive structure-activity relationship studies were performed allowing to hypothesize various TSPO pharmacophore models. The purpose of this paper is to highlight the structural requirements needed to obtain TSPO ligands with high affinity and selectivity.

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Section: Isoquinolinecarboxamide Derivativesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural Requirements to Obtain Highly Potent and Selective 18 kDa Translocator Protein (TSPO) Ligands

Taliani

Pugliesi²,

Settimo

2011

CTMC

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“…Among these radioligands, [11C]PK11195 remains the most cited radiotracer in this field and is still widely used, in spite of its low brain uptake and high level of non-specific binding (both leading to a poor signal-to-noise ratio) and its extensive binding to plasma proteins that complicates quantitative analysis of the receptor density [56]. Though the basic physiological role of PBR remains incompletely understood, its expression in the brain is currently the most reliable marker of neuroinflammation, which is linked to neuronal damage.…”

Section: Resultsmentioning

confidence: 99%

“…The previous exploration of the structure-affinity relationships (SAFIRs) concerning 4-phenyl-2-quinolinecarboxamide PBR ligands 2 showed as an interesting result the effect of the presence of a chlorine atom in the methylene carbon at position 3 of the quinoline nucleus [56]. Based on the subnanomolar PBR affinity shown by 3-chloromethyl derivative 2b, its chlorine atom was replaced by other halogens [e.g., fluorine(2a), bromine (2c), and iodine (2d), Fig.…”

Section: Quinoline-2-carboxamides Radioligandsmentioning

confidence: 99%

Radiolabelled Quinoline Derivaties for the PET Imaging of Peripheral Benzodiazepine Receptor

Lei

Wan²,

Zhan³

et al. 2012

CMIR

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Peripheral benzodiazepine receptor (PBR) has been implicated in the regulation of various cellular processes, including regulation of steroidogenesis,immunomodulation, porphyrin transport, heme synthesis, cell apoptosis and proliferation. Also, PBR expression levels were shown to be increased in a variety of cancers indicating its important role in cancer development. The investigation and biological evaluation of specific potent radioligands for positron emission tomography PET (Positron emission tomography) studies of PBRs are of great value as they have been associated with a variety of disease processes such as cancer, autoimmune diseases, viral infection, neurodegeneration,stress, and brain injury. More than twenty years have seen the development of radiolabelled quinoline derivaties (3-isoquinolinecarboxamide and quinoline-2-carboxamides) and some of these novel probes have been evaluated for the PET imaging of PBR. This mini review is aiming to provide a brief overview on the research on this kind of imiging probe.

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“…The process tolerates electron-withdrawing as well as electron-donating substituents on the a,b-ynone and arylboronic acid moieties. Substituents on the benzenic ring of quinoline can also be introduced (entry 12), and heteroarylboronic acids can be used as well (entries [8][9][10][11]. Moreover, the use of aryl-and vinyltrifluoroborate salts 5 is allowed (entries 5, 6, 14); the reactions of 1 with 5 were not optimized, and were carried out in the same manner as arylboronic acids.…”

Section: Methodsmentioning

confidence: 99%

Rh-Catalyzed Sequential Hydroarylation/Hydrovinylation-Heterocyclization of β-(2-Aminophenyl)-α,β-ynones with Organoboron Derivatives: A New Approach to Functionalized Quinolines

Abbiati¹,

Arcadi²,

Marinelli³

et al. 2006

Synlett

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4-Aryl and 4-vinyl quinolines were prepared via a sequential procedure involving regioselective Rh(acac)(C 2 H 2 )/dppfcatalyzed hydroarylation/hydrovinylation of b-(2-aminophenyl)-a,b-ynones with arylboronic acids or potassium aryl and vinyl trifluoroborates, followed by nucleophilic attack of the amino group onto the carbonyl.The quinoline scaffold is found in a variety of biologically active compounds, and quinoline-containing drugs are widely used in treatment of Plasmodium falciparum malaria. 1 Pharmacological studies on new quinoline derivatives appears frequently in current literature dealing with HIV-1 replication inhibition, 2 antimicrobial activity, 3 antihelmintic properties, 4 antimalarial activity 5 and inhibition of VEGF receptors; 6 in particular, 4-arylquinolines have been evaluated for their activity against West Nile Virus, 7 and have found application as ligands of peripheral benzodiazepine receptor. 8 Moreover, conjugated polymers incorporating a 2,4-diarylquinoline subunit are useful chemosensors for fluoride ion, 9 and 1,8-di(4-quinolyl)naphtalene derivatives are selective fluorescent sensors for metal ions in aqueous solution. 10 Consequently, there is a great current synthetic interest in assembling quinoline ring system from acyclic precursors. 11As a part of our ongoing efforts 12 to discover new routes to heterocycles starting from functionalized alkynes bearing proximate nucleophilic centers, we focused on b-(2-aminophenyl)-a,b-ynones 1 as useful building blocks for the synthesis of quinolines through sequential processes involving conjugate-addition-type 13 or cycloaddition 14 reactions followed by cyclization through nucleophilic attack of the amino group onto the carbonyl (cycloamination). In this context, we showed that the reaction of 1 with NaI in acetic acid affords 4-iodoquinolines 3. The potential of 3 as precursors for increasing molecular complexity via palladium-catalyzed reactions has been considered; 13 therefore, the combined addition of NaI to 1/palladiumcatalyzed Suzuki-Miyaura cross-coupling reaction 15 could represent a general entry into 4-aryl and 4-vinylquinolines. Indeed, the reaction of 1a with NaI in acetic acid gave the 4-iodoquinoline 3a (Scheme 1, a); subsequent cross-coupling with phenylboronic acid at room temperature 16 resulted in the formation of 4aa in good yield (Scheme 1, b). Scheme 1Nevertheless, the one-pot synthesis of 4-aryl and 4-vinylquinolines 4 starting from 1 represents a more interesting challenge. 17 In order to achieve this goal , we investigated the development of a one-pot/two-step synthetic protocol. NaI (2 equiv) was added to 1a in ethanol at 80°C in the presence of 1 equivalent of TsOH; after the complete conversion of 1a to 3a (3 h), PhB(OH) 2 (1.3 equiv), K 3 PO 4 (3 equiv), Pd(OAc) 2 (0.03 equiv) and TBAB (0.08 equiv) were added to the reaction mixture allowing the formation of 4a in 47% overall yield after 6 hours at 80°C (Scheme 1, c). Probably there is room for optimization; however, the main drawback of this procedure is const...

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Structure−Activity Relationships in Carboxamide Derivatives Based on the Targeted Delivery of Radionuclides and Boron Atoms by Means of Peripheral Benzodiazepine Receptor Ligands

Cited by 38 publications

References 20 publications

Structural Requirements to Obtain Highly Potent and Selective 18 kDa Translocator Protein (TSPO) Ligands

Structural Requirements to Obtain Highly Potent and Selective 18 kDa Translocator Protein (TSPO) Ligands

Radiolabelled Quinoline Derivaties for the PET Imaging of Peripheral Benzodiazepine Receptor

Rh-Catalyzed Sequential Hydroarylation/Hydrovinylation-Heterocyclization of β-(2-Aminophenyl)-α,β-ynones with Organoboron Derivatives: A New Approach to Functionalized Quinolines

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