Chemical Delivery System of MIBG to the Central Nervous System: Synthesis, 11 C-Radiosynthesis, and in Vivo Evaluation

Fabienne Gourand , Delphine Patin , Axelle Henry , Meźiane Ibazizeǹe , Martine Dhilly , Fabien Fillesoye , Olivier Tirel , Mihaela-Liliana Tintas , Cyril Papamicael , Vincent Levacher (1) , Louisa Barré , Med Acs

1 COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse

The norepinephrine transporter (NET) plays an important role in neurotransmission and is involved in a multitude of psychiatric and neurodegenerative diseases. [123I/131I]meta-iodobenzylguanidine (MIBG) is a widely used radiotracer in the diagnosis and follow-up of peripheral neuroendocrine tumors overexpressing the norepinephrine transporter. MIBG does not cross the blood–brain barrier (BBB), and we have demonstrated the “proof-of-concept” that 1,4-dihydroquinoline/quinolinium salt as chemical delivery system (CDS) is a promising tool to deliver MIBG to the brain. To improve BBB passage, various substituents on the 1,4-dihydroquinoline moiety and a linker between CDS and MIBG were added. A series of CDS-MIBG 1a–d was synthesized, labeled with carbon-11, and evaluated in vivo into rats. The in vivo results demonstrated that, although adding substituents on CDS in 1a–c is of no benefit for brain delivery of MIBG, the presence of a linker in CDS-MIBG 1d greatly improved both brain penetration and the release rate of MIBG in the central nervous system.

Mots clés: 1, MIBG, 4-dihydroquinolines carriers, redox chemical delivery system, radiosynthesis, norepinephrine transporter, Central nervous system

Domaines: Chimie; Chimie thérapeutique

Fabienne Gourand, Delphine Patin, Axelle Henry, Meźiane Ibazizeǹe, Martine Dhilly, et al.. Chemical Delivery System of MIBG to the Central Nervous System: Synthesis, 11 C-Radiosynthesis, and in Vivo Evaluation. ACS Medicinal Chemistry Letters, 2019, 10 (3), pp.352-357. ⟨10.1021/acsmedchemlett.8b00642⟩. ⟨hal-03020265⟩