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Tesi etd-05202015-125103

Thesis type
Tesi di laurea magistrale LM5
Design and synthesis of novel quinoline based TSPO ligands
Corso di studi
relatore Prof.ssa Taliani, Sabrina
relatore Dott.ssa Barresi, Elisabetta
Parole chiave
  • TSPO
  • quinoline
Data inizio appello
Data di rilascio
Riassunto analitico
The 18kDa Translocator Protein (TSPO) was discovered as peripheral binding site for the benzodiazepine diazepam and initially named “Peripheral-type benzodiazepine receptor” (PBR). This protein is mainly located at the contact sites between the outer and the inner mitochondrial membranes, and is strictly associated with a number of proteins to form the mitochondrial permeability transition pore (MPTP). It is involved in a variety of biological processes including cholesterol transport, steroidogenesis, cell growth and differentiation, apoptosis induction, and regulation of immune functions.
The expression of TSPO is ubiquitary in peripheral tissues (steroid producing tissues, liver, heart, kidney, lung, immune system), and in the central nervous system is mainly located in glial cells and in neurons. Many studies have reported that the basal expression of TSPO is up-regulated in a number of neuropathologies, including gliomas and neurodegenerative disorders (Huntington’s and Alzheimer’s diseases), in various forms of brain injury and inflammation, as well as in a variety of tumors; furthermore, a decrease in TSPO levels have been found in anxiety and mood disorders.
Consequently, TSPO has been suggested as a promising diagnostic marker to image and measure the TSPO expression and distribution levels and thus for evaluation of disease progression.
Actually, a virtual screaning study was conducted by Tuccinardi et al. in order to identify new leads able to bind TSPO. From this study 38 compounds were selected and among these seven compounds showed high affinity for TSPO. Among these we focused on compound NRB03635 which showed Ki value in the nanomolar range.
Interestingly, this compound is also structurally related to quinazoline carboxamide derivatives I previously synthesized by the research group I work with during my thesis period, which showed high affinity and selectivity for TSPO . It is also structurally related to the known high affinity TSPO ligand 2-phenylquinoline carboxamide derivatives II, recently described by the research group of Pike, in order to develop new leads to pet radioligands for the Traslocator protein.

1: Tiziano Tuccinardi, Sabrina Taliani, Marusca Bellandi, Federico Da Settimo, Eleonora Da Pozzo, Claudia Martini, and Adriano Martinelli. Med.Chem.2009, 4, 1686-1694.
Castellano S.; Taliani S.; Milite C.; Pugliesi I.; Da Pozzo E.; Rizzetto E.; Bendinelli S.; Costa B.; Cosconati S.; Greco G.; Novellino E.; Sbardella G.; Stefancich G.; Martini C.; Da Settimo F., J.Med.Chem 2012, 55 , 4506-4510.
Castellano S.; Taliani S.; Viviano M.; Milite C.; Da Pozzo E.; Costa B.; Barresi E.; Bruno A.; Cosconati S.; Marinelli L.; Greco G.; Novellino E. Sbardella G.; Da Settimo F.; Martini C., J.Med.Chem. 2014, 57 , 2413-2428.
Brouwer C.; Jenko K.; Zoghbi S.; Innis R.; Pike V.; J. Med.Chem, 2014, 57, 6240-6251.