Total Radiosynthesis: Thinking outside "the box".

Area of Science:

• Radiochemistry
• Medicinal Chemistry
• Synthetic Organic Chemistry

Background:

• Positron emission tomography (PET) molecular imaging faces challenges in radiopharmaceutical synthesis due to limited labeled reagents and radiosynthetic methods.
• Short-lived radionuclides like carbon-11 (¹¹C) and fluorine-18 (¹⁸F) are crucial but difficult to incorporate efficiently into complex molecules.
• Current radiopharmaceutical production often relies on late-stage incorporation, limiting multi-step reactions and exploration of novel tracers.

Purpose of the Study:

• To introduce the concept of 'total radiosynthesis' inspired by total synthesis logic to overcome limitations in radiopharmaceutical development.
• To accelerate the discovery pipeline for novel radiotracers for in vivo imaging studies.
• To develop efficient and diverse radiosynthetic methods for labeling complex molecules with short-lived radionuclides.

Main Methods:

• Applying retrosynthetic analysis and multi-step reaction strategies to radiopharmaceutical synthesis.
• Developing novel methods for ¹¹C and ¹⁸F radiolabeling, including [¹¹C]CO₂ fixation and labeling non-activated arenes via iodonium ylides.
• Utilizing automation technologies such as microfluidic flow chemistry and rapid purification for radiopharmaceutical production.

Main Results:

• Demonstrated the suitability of multi-step radiochemical reactions for preclinical and clinical PET imaging.
• Enabled 'library radiosynthesis' and labeling of previously inaccessible molecules.
• Developed methods for human PET imaging using novel radiotracers.

Conclusions:

• Total radiosynthesis offers a transformative approach to radiopharmaceutical development, expanding the scope of accessible PET tracers.
• This paradigm shift accelerates the evaluation of potential drug candidates and diagnostic agents.
• The developed strategies are crucial for advancing molecular imaging and personalized medicine.