REVIEW P ET imaging has several distinct properties that make it a powerful tool in the age of precision medicine (1–3). Tis noninvasive imaging technique can provide information on disease burden for the whole body. Ad- ditionally, imaging can provide results on drug uptake in the targeted and healthy tissues and can enable early assessment of the risk and beneft of the treatment (4). For example, the combination of an imaging agent with a traditional pharmaceutical or radiation therapy (ie, a theranostic pair) allows physicians to tailor the treat- ment on the basis of an individual’s response (5–7). Furthermore, the development of improved PET imag- ing capabilities will provide the opportunity to measure the complete pharmacokinetics and pharmacodynam- ics of targeted cancer drugs by using positron-emitting radionuclide-labeled drugs or analogs. In the past decade, PET radiotracers have shown promise in preclinical models of cancer, including prostate, breast, and many other types, and some have crossed the threshold to clinical translation to obtain regulatory approval from the Food and Drug Admin- istration (FDA), such as the recent examples of fuo- rine 18 ( 18 F) fuoroestradiol (Cerianna) for breast can- cer and 18 F fuciclovine (Axumin) for prostate cancer. However, the steps needed for the identifcation of a new radiotracer for translational PET imaging stud- ies is an expensive and time-consuming process (8). Hung (9) and Harapanhalli (10) published review ar- ticles on the current state and regulatory consideration for PET radiotracer development. For PET radiotrac- ers that are generally considered safe and efective, such as a radioactive version of a known substance or drug, clinical trials may be conducted under an insti- tutional approval via the Radioactive Drug Research Committee (11). Mosessian et al (12) have also pre- sented an example of an investigational new drug (IND) submission and early clinical evaluation of 18 F fuoro-arabinofuranosylcytosine. In recent years, there have been a number of PET radiotracers, including 18 F PARP inhibitor (PARPi), 18 F fuorthanatrace ( 18 F-FTT), and 18 F olaparib, that have been developed for imaging poly (adenosine di- phosphate–ribose) polymerase-1 (PARP-1) expression levels in patients with cancer. Te development and evaluation of these radiotracers were reviewed by Pu- entes et al (13). Te authors discussed 10 radiotrac- ers targeting PARP-1 presented in the literature in the past 5 years. Of these, only 18 F-FTT has been used in translational imaging studies in a variety of tumor types, including hepatocellular carcinoma and breast and ovarian cancer (14–16). In this report, we present a detailed description of the development of 18 F-FTT as a PET-based biomarker for imaging PARP-1 expres- sion levels in patients with cancer. To illustrate this process, we have focused on the following steps: (a) identifcation of PARP-1 as a target for PET imaging studies, (b) identifcation of lead radiotracers, (c) pre- clinical evaluation and validation of 18 F-FTT as a PET radiotracer for imaging PARP-1, (d) steps in the regu- latory process to enable frst-in-human studies, and (e) single-site (phase 0 or 1) and (f) multicenter (phase 2) clinical trials. A fowchart demonstrating the steps for This copy is for personal use only. To order printed copies, contact reprints@rsna.org Fluorine 18 ( 18 F) fuorthanatrace ( 18 F-FTT) is a PET radiotracer for imaging poly (adenosine diphosphate–ribose) polymerase-1 (PARP-1), an important target for a class of drugs known as PARP inhibitors, or PARPi. Tis article describes the stepwise develop- ment of this radiotracer from its design and preclinical evaluation to the frst-in-human imaging studies and the initial validation of 18 F-FTT as an imaging-based biomarker for measuring PARP-1 expression levels in patients with breast and ovarian cancer. A detailed discussion on the preparation and submission of an exploratory investigational new drug application to the Food and Drug Administration is also provided. Additionally, this review highlights the need and future plans for identifying a commercialization strategy to overcome the major fnancial barriers that exist when conducting the multicenter clinical trials needed for approval in the new drug application process. Te goal of this article is to provide a road map that scientists and clinicians can follow for the successful clinical translation of a PET radiotracer developed in an academic setting. © RSNA, 2022 The Development of 18 F Fluorthanatrace: A PET Radiotracer for Imaging Poly (ADP-Ribose) Polymerase-1 Hsiaoju S. Lee, PhD • Sally W. Schwarz, MS • Erin K. Schubert, BS • Delphine L. Chen, MD • Robert K. Doot, PhD • Mehran Makvandi, PharmD • Lilie L. Lin, MD • Elizabeth S. McDonald, MD, PhD • David A. Mankof, MD, PhD • Robert H. Mach, PhD From the Department of Radiology, Perelman School of Medicine, University of Pennsylvania, 231 S 34th St, Vagelos Laboratories, Room 1012, Philadelphia, PA 19104- 6323 (H.S.L., E.K.S., R.K.D., M.M., E.S.M., D.A.M., R.H.M.); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (S.W.S.); Department of Radiology, University of Washington School of Medicine, Seattle, Wash (D.L.C.); and Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Tex (L.L.L.). Received July 1, 2021; revision requested August 30; revision received October 11; accepted December 23. Address correspondence to R.H.M. (e-mail: rmach@pennmedicine.upenn.edu). Authors declared no funding for this work. Conficts of interest are listed at the end of this article. Radiology: Imaging Cancer 2022; 4(1):e210070 • https://doi.org/10.1148/rycan.210070 • Content codes: