Synthesis of three alpha 7 agonists in labeled form

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Neuroscience

Background:

• Development of novel therapeutics for Alzheimer's disease (AD) is a critical unmet medical need.
• Alpha 7 nicotinic acetylcholine receptor agonists are a promising therapeutic strategy for AD.
• Radiolabeled compounds are essential for pharmacokinetic and metabolic studies of drug candidates.

Purpose of the Study:

• To synthesize radiolabeled forms of three drug candidates (1, 2, and 3) for Alzheimer's disease research.
• To investigate the synthetic routes and labeling strategies for these compounds.

Main Methods:

• Synthesis of C-14 labeled compound 1 via lithiation and coupling.
• Investigation of deuterium labeling on compound 1, revealing a primary isotope effect.
• Development of an alternative labeling strategy for [(2)H4]-1.
• Multi-step synthesis of [(13)C5]-2 and [(14)C2]-3 using different starting materials.

Main Results:

• Successful preparation of C-14 labeled compound 1.
• Discovery of a significant primary isotope effect during deuterium labeling of compound 1, altering the reaction pathway.
• Efficient synthesis of [(13)C5]-2 and [(14)C2]-3 through distinct synthetic routes.

Conclusions:

• The synthetic strategies for preparing labeled drug candidates 1, 2, and 3 were established.
• The observed primary isotope effect highlights the importance of considering reaction mechanisms in synthetic planning for labeled compounds.
• These labeled compounds will facilitate further preclinical evaluation of their potential as Alzheimer's disease treatments.