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

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.

Delivering FLT to the Central Nervous System by Means of a Promising Targeting System: Synthesis, [11C]Radiosynthesis, and in Vivo Evaluation.

The development of delivery systems to transport some specific radiotracers across the blood-brain barrier (BBB) needs to be investigated for brain imaging. [18F]FLT (3'-deoxy-3'-18F-fluoro-l-thymidine), an analogue substrate of the nucleoside thymidine, has been developed as a proliferation tracer for oncological PET studies. Unfortunately, low-grade brain tumors are poorly visualized due to the low uptake of [18F]FLT in brain tissue, preventing its use in PET imaging to detect brain tumors at an early stage. Based on our previous work, a redox chemical delivery system (CDS) related to Bodor's strategy was developed to enable the penetration of FLT into the brain. To this end, FLT was covalently linked to a series of lipophilic carriers based on a 1,4-dihydroquinoline structure. To determine the best carrier, various sets of [11C]CDS-FLT were prepared and injected into rats. Pleasingly, in vivo results let us suggest that this CDS is a promising approach to overcome the BBB to target low-grade brain tumors for PET imaging.