Carborane-conjugated 2-quinolinecarboxamide ligands of the translocator protein for boron neutron capture therapy

Andrea Cappelli; Salvatore Valenti; Alessandra Mancini; Germano Giuliani; Maurizio Anzini; Saverio Altieri; Silva Bortolussi; Cinzia Ferrari; Anna Maria Clerici; Cecilia Zonta; Fabio Carraro; Irene Filippi; Gianluca Giorgi; Alessandro Donati; Sandra Ristori; Salvatore Vomero; Alessandra Concas; Giovanni Biggio

doi:10.1021/bc100195s

Carborane-conjugated 2-quinolinecarboxamide ligands of the translocator protein for boron neutron capture therapy

Bioconjug Chem. 2010 Dec 15;21(12):2213-21. doi: 10.1021/bc100195s. Epub 2010 Nov 18.

Authors

Andrea Cappelli¹, Salvatore Valenti, Alessandra Mancini, Germano Giuliani, Maurizio Anzini, Saverio Altieri, Silva Bortolussi, Cinzia Ferrari, Anna Maria Clerici, Cecilia Zonta, Fabio Carraro, Irene Filippi, Gianluca Giorgi, Alessandro Donati, Sandra Ristori, Salvatore Vomero, Alessandra Concas, Giovanni Biggio

Affiliation

¹ Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy. cappelli@unisi.it

PMID: 21087014
DOI: 10.1021/bc100195s

Abstract

Potential boron neutron capture therapy (BNCT) agents have been designed on the basis of the evidence about translocator protein (TSPO) overexpression on the outer mitochondrial membrane of tumor cells. The structure of the first TSPO ligand bearing a carborane cage (compound 2d) has been modified in order to find a suitable candidate for in vivo studies. The designed compounds were synthesized and evaluated for their potential interaction with TSPO and tumor cells. In vitro biological evaluation showed in the case of fluoromethyl derivative 4b a nanomolar TSPO affinity very similar to that of 2d, a significantly lower cytotoxicity, and a slightly superior performance as boron carrier toward breast cancer cells. Moreover, compound 4b could be used as a ¹⁹F magnetic resonance imaging (MRI) agent as well as labeled with ¹¹C or ¹⁸F to obtain positron emission tomography (PET) radiotracers in order to apply the "see and treat" strategy in BNCT.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / diagnostic imaging
Adenocarcinoma / pathology
Adenocarcinoma / radiotherapy
Animals
Binding Sites
Boranes / chemical synthesis
Boranes / pharmacology
Boranes / therapeutic use
Boron Neutron Capture Therapy / methods*
Boron* / chemistry
Boron* / metabolism
Brain / drug effects*
Brain / metabolism
Brain / pathology
Breast Neoplasms / diagnostic imaging
Breast Neoplasms / pathology
Breast Neoplasms / radiotherapy
Carrier Proteins / chemistry
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Cell Line, Tumor
Colonic Neoplasms / diagnostic imaging
Colonic Neoplasms / pathology
Colonic Neoplasms / radiotherapy
Crystallography, X-Ray
Female
Fluorine Radioisotopes
Gene Expression
Magnetic Resonance Imaging
Male
Mitochondria / drug effects*
Mitochondria / metabolism
Mitochondria / pathology
Models, Molecular
Positron-Emission Tomography
Protein Binding
Quinolines* / chemical synthesis
Quinolines* / pharmacology
Quinolines* / therapeutic use
Rats
Receptors, GABA-A / chemistry
Receptors, GABA-A / genetics
Receptors, GABA-A / metabolism*
Structure-Activity Relationship

Substances

2-quinolinecarboxamide
Boranes
Carrier Proteins
Fluorine Radioisotopes
Quinolines
Receptors, GABA-A
Tspo protein, rat
Boron