Short-wave infrared Cerenkov imaging to better visualize targeted radiotherapy and diagnostic radiotracers

SUMMARY. The problem: Cerenkov luminescence (CL) imaging (CLI) is a new imaging method that utilizes light emitted during decay of radiotracers. CLI merges optical and nuclear imaging by utilizing affordable yet highly sensitive optical cameras with clinical radiotracers. It provides fast and cheap clinical optical imaging to explore radiotracer distribution in patients. While not tomographic, CLI systems have a lower price, smaller footprint and higher resolution than nuclear imaging scanners. Yet, due to the very low signal intensity of CL its versatility remains limited since CLI requires strict exclusion of ambient light with an enclosure. Therefore, CLI requires novel approaches to make clinical imaging more feasible. We hypothesized that we could explore the short-wave infrared (SWIR) part of CL to enable CLI under ambient light without enclosure, providing improved and facile CLI, particularly of isotopes used for therapy that cannot be imaged otherwise. SWIR imaging (900- 1300 nm) has almost no autofluorescence, absorption or scatter but provides significantly higher depth penetration, yielding images with higher contrast and resolution compared to the visible range. Since typical LEDs do not emit light beyond 850 nm, they do not interfere with the SWIR camera. We can therefore perform CLI in the SWIR range (SWIR-CLI) without the limiting light-tight box and under ambient LED light and also achieve better signal penetration and accuracy. We will investigate if SWIR-CLI can be used to monitor distribution of therapeutic isotopes for targeted radiotherapy (TRT), a fast-expanding field as highlighted by Novartis’ acquisition of Lutathera and Pluvicto for the price of $6 bn. These agents are targeting 177Lu as therapy to neuroendocrine and prostate cancers. For TRT α-emitting isotopes are particularly attractive due to the α- particle’s short path length with high linear energy transfer. However, α-emitters are very difficult to image with conventional equipment. The α-emitter could be swapped with an imaging isotope, but this can alter the agent’s biodistribution. The α-particle itself does not have sufficient energy to produce CL but several daughters in the decay chains of most α-emitters produce electrons with sufficient energy to create CL. We have already imaged the α-emitter 223Ra in patients and have recently shown that CLI of α-emitters in the SWIR is possible. SWIR- CLI could therefore provide a facile imaging approach for α-emitters. We will answer with our three independent Aims the following questions: (1) Can we image diagnostic isotopes with SWIR-CLI? (2) Can we image therapeutic emitters with SWIR-CLI? (3) Can we use SWIR-CLI to image patients undergoing PET and/or TRT? Animal studies will employ established mouse cancer models to optimize imaging parameters and validate findings, directly informing the co-clinical Aim 3 trial. By eliminating the requirement for a light-tight enclosure and enabling CLI under ambient light, SWIR-CLI represents a significant shift in the practical deployment of CLI rather than an incremental improvement. Our study will broaden the reach of CLI by enabling imaging under ambient lighting, unlocking innovative new opportunities for CLI (monitoring TRT) in research & clinical settings. Project Number: 1R01CA313953-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Jan Grimm | Institution: SLOAN-KETTERING INST CAN RESEARCH, NEW YORK, NY | Award Amount: $644,423 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 ISB-T (03)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11381573