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Radiotracer Targeting of the Colony Stimulating Factor 1 Receptor Enables the Identification of Peripheral Nerve Injuries and Monitoring of Axonal Regeneration
Jeffrey Khong, BS, John D. Nguyen, DO, Rachana Suresh, MBBS, MPH, Zachary Zamore, BA, Jared Zhang, ScB, Fares Lebbos, MD, Christopher Erb, BS, Samarth Krishna, MBBS, MPH, Arman Zadeh, MS, Claire Hao, BS, Mohammed Shahid, MD, Alec J. Chen, MS, Hyojin Cha, PhD, Andrew Horti, PhD, Catherine A Foss, PhD, William Padovano, MD, MPHS; Sami H. Tuffaha, MD
Johns Hopkins University School of Medicine, Baltimore, MD
Introduction: Visualizing axonal regeneration along injured nerves is not possible with current imaging modalities, severely limiting accurate diagnosis and effective management of peripheral nerve injuries. We sought to target macrophages, which infiltrate damaged nerves during Wallerian degeneration, to non-invasively characterize nerve injuries. Specifically, we evaluated the use of PET agents [
11C]CPPC and [
18F]JHU1221683 (an
18F analogue of [
11C]CPPC), which bind to the colony stimulating factor 1 receptor (CSF1R) expressed by proliferating macrophages, as novel nerve-imaging agents.
Materials & Methods: Twenty-eight male Lewis rats underwent either unilateral sciatic nerve transection with repair using a 3cm isograft or transection without repair, in which the isograft was coapted only to the distal stump. Two- and four-weeks post-intervention, animals received intravenous [
11C]CPPC or [
18F]JHU1221683 and were sacrificed 30 minutes post-injection. To confirm binding specificity, increasing doses of unlabeled CPPC were administered to 8 animals prior to radiotracer injection. Radioactivity was quantified with an automated gamma counter and expressed as percent injected dose per gram (%ID/g) and standardized uptake values (SUVs). To examine differential uptake, nerves were analyzed in 4 segments: proximal sciatic, proximal and distal graft, and distal sciatic. Kruskal-Wallis and post-hoc Dunn tests compared uptake between groups.
Results: Relative to sham, sciatic nerve segments distal to the injury site from both unrepaired and repaired animals had significantly greater uptake at both 2 weeks (p<0.05) and 4 weeks (p<0.05). Uptake in both unrepaired and repaired segments distal to the injury site was significantly greater than in segments proximal to the injury site (p<0.05). Compared to 2 weeks, uptake in distal segments at 4 weeks decreased by 26% in repaired nerves (p<0.05) and remained constant in unrepaired nerves (p>0.05). Proximal and distal nerve segments demonstrated 90% (p<0.05) and 82% (p<0.05) reduced radioactivity following CSF1R blockade with high-dose unlabeled CPPC.
Conclusion: [
18F]JHU1221683 and [
11C]CPPC effectively labeled macrophage content within injured nerves with high specificity, demonstrating higher uptake in distal versus proximal segments and in unrepaired versus repaired nerves. These findings suggest that [
11C]CPPC and [
18F]JHU1221683 PET imaging of CSF1R may be a promising non-invasive approach for identifying peripheral nerve injuries and monitoring axonal regeneration following repair.
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