Clinical Translation of the First Meitner-Auger PET Theranostic

Prostate cancer is the most common non-cutaneous malignancy diagnosed in men. Disseminated disease is incurable and metastatic castrate resistant prostate cancer (mCRPC) is a leading cause of cancer death. Systemically administered radiopharmaceuticals can localize ionizing radiation to all sites of metastatic disease and have recently been approved for mCRPC. However, only modest progression free and overall survival benefits have been realized. Quantitative imaging of the radiotherapy distribution can be used to guide optimal use and to maximize therapeutic index. This theranostic approach, when used with high linear energy transfer emissions produce irreparable DNA damage, can guide precision treatment. Meitner-Auger electron (MAe-) emitters deposit high absorbed doses in circumscribed fields at the sub-micron scale. This spares distant normal tissue, but requires that decay occurs directly upon critical cancer cell structures. Chelator dependent radiometal agents typically cannot access the nucleus, and labile halogens are avoided because of instability. Here, we investigate the first-in-man clinical imaging of a stable bromine-77 ligand that targets an abundant genome-associate target: PARP1. The drug, [77Br]Br-WC-DZ, has subnanomal affinity for PARP1 and is produced in 15 min using a single-step with high yield and purity. Through novel observations, we reveal for the first time that bromine-77 can be used with clinical positron emission tomography systems for high resolution, high sensitivity and quantitative imaging. Together, the high linear energy profile and quantitative imaging features of this DNA-targeted theranostic result in significant anticancer therapeutic potential. We propose translation and evaluation of [77Br]Br-WC-DZ in men with mCRPC to assess feasibility, distribution and imaging characteristics. Simulations and experimental phantom acquisitions are used to optimize image quality and clinical protocol, in Specific Aim 1. In Aim 2, we perform eIND enabling studies of tolerability and absorbed dose. In Aim 3, we initiate an Early Phase I study to assess the safety and distribution of this longer- lived [77Br]Br-WC-DZ (56 h), and then evaluate the complementary information from a PARP1 targeted agent with conventional F-18 (0.9 h; [18F]-FTT). This trial provides input data for further precision image-guided therapeutic intervention of this potent therapy. We leverage the expertise and experience of the team along with institutional strengths in PET tracer development, translation and analysis. This group of investigators and the strength of our data addresses key issues in prostate cancer radiopharmaceutical deployment and demonstrate the potential to realize the transformative capabilities of molecularly targeted radiotherapy for men suffering from mCRPC. Project Number: 1R01CA311209-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Daniel Thorek (+2 co-PIs) | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $641,419 | Activity Code: R01 | Study Section: Clinical Translational Imaging Science Study Section[CTIS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11333933