# Copper-mediated Radiofluorination: from Proof-of-Concept to Clinical Impact

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $377,343

## Abstract

Abstract: Radiotracers containing [18F]-labeled electron-rich aromatic rings are among the most highly sought-
after PET imaging agents but have been historically challenging to synthesize. Recent efforts have sought to
improve the late-stage labeling of (hetero)arenes with [18F]fluoride. In particular, transition metal-mediated
reactions using high molar activity [18F]fluoride have changed the way radiochemists form C–18F bonds, and
copper-mediated radiofluorination (CMRF) has proven one of the most versatile of approaches. In the previous
award, we reported 10 new CMRF reactions, validated them for Good Manufacturing Practice (GMP), and used
them to synthesize FDA-approved clinical doses. However, despite many successes, several key challenges
remain for the widespread clinical application of CMRF: (a) many important organic scaffolds are incompatible
with existing CMRF processes, (b) yields of automated CMRF methods are typically moderate and thus
unsuitable for commercial distribution, and (c) disposable cassette technologies are not available for CMRF on
automated radiosynthesizers, limiting radiotracer production for routine clinical use. All of these challenges will
be addressed in this renewal proposal. The overall objective is to develop robust methods for clinical production
of diverse PET radiotracers. Our central hypothesis is that CMRF is uniquely positioned to enable us to achieve
this goal. The proposed research will identify new reactions to radiofluorinate scaffolds that are incompatible with
existing CMRF (Aim 1), use cutting edge machine learning techniques to improve automated CMRF yields (Aim
2), and develop cassette technologies for reliable GMP production of clinical radiotracers using CMRF (Aim 3).
The research is significant because it entails development of methods for radiolabeling bioactive molecules
containing functionality that is incompatible (or low yielding) with existing CMRF (heterocycles like pyridine and
morpholine, drug molecules like GW405833), as well as optimized automated methods and cassettes for
radiotracers that have been challenging to access for decades (e.g. [18F]FDOPA). The viability of the proposed
efforts is supported by extensive preliminary results that provide groundwork for the exciting new research
directions. Our team has been collaborating for 7 years and our expertise in transition metal catalysis (Sanford),
radiochemistry (Scott), and machine learning (Doyle) uniquely positions us to accomplish the proposed research.
The project goals will be accomplished through a variety of innovations including: (1) developing methods for
labeling challenging electron-rich (hetero)arenes from new precursors (C–H bonds, aryl halides), (2) the first
application of machine learning to radiochemistry, and (3) development of automated cassettes for conducting
CMRF using the newest generation of radiosynthesizers designed for plug-and-play production. Overall, this
project will deliver multiple new methods ...

## Key facts

- **NIH application ID:** 10439762
- **Project number:** 5R01EB021155-06
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MELANIE S. SANFORD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $377,343
- **Award type:** 5
- **Project period:** 2016-09-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439762

## Citation

> US National Institutes of Health, RePORTER application 10439762, Copper-mediated Radiofluorination: from Proof-of-Concept to Clinical Impact (5R01EB021155-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10439762. Licensed CC0.

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