PT - JOURNAL ARTICLE AU - Jingjing Zhang AU - Deling Li AU - Gang Niu AU - Richard Baum AU - Zhaohui Zhu AU - Xiaoyuan Chen TI - <strong>First-in-Human Study of a<sup>64</sup>Cu-Labeled Long-acting Integrin αvβ3 Targeting Molecule<sup>64</sup>Cu-NOTA-EB-RGD in Healthy Volunteers and GBM Patients</strong><strong/> DP - 2020 May 01 TA - Journal of Nuclear Medicine PG - 349--349 VI - 61 IP - supplement 1 4099 - http://jnm.snmjournals.org/content/61/supplement_1/349.short 4100 - http://jnm.snmjournals.org/content/61/supplement_1/349.full SO - J Nucl Med2020 May 01; 61 AB - 349Objectives: This study aimed to explore the safety, biodistribution and dosimetry of a long-acting integrin αvβ3-targeted PET tracer 64Cu-NOTA-EB-RGD in humans, and to assess the pharmacokinetics and diagnostic feasibility of 64Cu-NOTA-EB-RGD in glioblastoma multiforme (GBM) patients. Methods: Following institutional review board approval and informed consent, three healthy volunteers (2 male and 1 female) underwent whole-body PET/CT at 0.5, 1.0, 8.0, 12.0 and 24.0 hours after a bolus injection of 64Cu-NOTA-EB-RGD (148-296 MBq [4-8 mCi]). Safety data were collected before, 1 day and 1 week after the injection, including vital signs (blood pressure, pulse rate, respiratory frequency, and temperature), physical examination, electrocardiography, laboratory parameters (blood biochemistry, hematologic, kidney and liver function tests), and adverse events. Regions of interest were drawn manually over major organs, and time-activity curves were obtained. Dosimetry was calculated using the OLINDA/EXM software. 64Cu-NOTA-EB-RGD was also administered to a patient with recurrent GBM. Seven sets of brain PET or PET/CT scans of the patient were acquired over two consecutive days. The time points of image acquisition were 30 min, 1 h, 8 h, 12 h, 20 h, 20.5 h and 24 h after injection of the radiopharmaceutical. Tumor-to-background ratios (TBR) were calculated using volume of interest (VOI) based SUVmax and SUVmean for target tumor lesion and SUVmean for normal brain tissue as the background. Within 1 week after tracer administration, the patient underwent surgical treatment and immunohistochemical staining of tumor samples against integrin αvβ3 was performed. Results: The administration of 64Cu-NOTA-EB-RGD was well tolerated, with no adverse symptoms or signs being noticed or reported either immediately or up to 1 week after the administration. 64Cu-NOTA-EB-RGD uptake at 1 h p.i. was seen in the blood pool, kidneys, and bladder, with low accumulation in other normal organs. The organ with the highest radiation dose was the urinary bladder. The mean effective dose and effective dose equivalent of 64Cu-NOTA-EB-RGD were 0.0315 mSv/MBq ± 0.0052 and 0.0454 mSv/MBq ± 0.0088, as compared to the previously reported 68Ga-NOTA-PRGD2 of 0.0226 mSv/MBq and 0.0277 mSv/MBq, respectively, and an effective dose of 0.0315 mSv/MBq (0.1166 rem/mCi) represents exposure of 0.933 rem for a subject injected with 8 mCi, which was very similar to an 18F-FDG PET scan. The mean absorbed dose of kidneys and red marrow of 64Cu-NOTA-EB-RGD were 0.0994 mSv/MBq ± 0.0425 and 0.0230 mSv/MBq ± 0.0027.Injection of 64Cu-NOTA-EB-RGD to the patient with recurrent GBM showed high accumulation at the tumor which increased over time, reaching SUVmax of 6.25 at 12 h p.i., and decreased slightly by 24 h, but with continuously increased tumor-to-background (unaffected brain area) contrast over time. TBR ratio based on SUVmaxand SUVmean reached a maximum of 73.4 and 40.2 at 24 h p.i., respectively. Post-operative pathology revealed WHO grade IV glioblastoma multiforme and immunohistochemical staining showed moderate expression of integrin αvß3. Conclusions: This first-in-human study indicates the safety, favorable pharmacokinetic and dosimetry profile of a new type of PET tracer using a relatively long half-life PET isotope 64Cu-labeled long-acting integrin αvβ3-targeted molecule EB-RGD. By introducing an EB-derived albumin-binding moiety to enhance tumor uptake, 64Cu-NOTA-EB-RGD provides a superior pharmacokinetics and high contrast for diagnostic imaging purposes in GBM patient. The results shown here for 64Cu-labeled EB-RGD are promising and very attractive for theranostic applications like 67Cu, 177Lu, 90Y or 225Ac as therapeutic counterparts. Further investigations with matched pairs of copper and other therapeutic agents are warranted. View this table:Dosimetry calculation for 64Cu-NOTA-EB-RGD (mSv/MBq, n = 3, 2 males and 1 female)