First-in-Human Study of 68 Ga-DOTA-Siglec-9, PET Ligand Targeting Vascular Adhesion Protein 1

Abstract

Sialic acid-binding immunoglubulin-like lectin 9 (Siglec-9) is a ligand of vascular adhesion protein 1 (VAP-1). A gallium 68-labeled peptide of Siglec-9, ⁶⁸Ga-DOTA-Siglec-9, holds promise as a novel PET tracer for imaging of inflammation. This first-in-human study investigated the safety, tolerability, biodistribution, and radiation dosimetry of this radiopharmaceutical. <b>Methods:</b> Six healthy males underwent dynamic whole-body PET/CT. Serial venous blood samples were drawn from 1-240 min after intravenous injection of 162 ± 4 MBq of ⁶⁸Ga-DOTA-Siglec-9. In addition to gamma counting, the plasma samples were analyzed by high-performance liquid chromatography to detect intact tracer and radioactive metabolites. Radiation doses were calculated using the OLINDA/EXM 2.2 software. In addition, a patient with early rheumatoid arthritis was studied with both ⁶⁸Ga-DOTA-Siglec-9 and ¹⁸F-FDG PET/CT to determine the ability of the new tracer to detect arthritis. <b>Results:</b> ⁶⁸Ga-DOTA-Siglec-9 was well tolerated by all subjects. ⁶⁸Ga-DOTA-Siglec-9 was rapidly cleared from blood circulation and several radioactive metabolites were detected. The organs with the highest absorbed doses were the urinary bladder wall (0.38 mSv/MBq) and kidneys (0.054 mSv/MBq). The mean effective dose was 0.022 mSv/MBq (range 0.020-0.024 mSv/MBq). Most importantly, however, 68Ga-DOTA-Siglec-9 was able to detect arthritis comparable to ¹⁸F-FDG. <b>Conclusion:</b> Intravenous injection of ⁶⁸Ga-DOTA-Siglec-9 was safe and biodistribution is favorable for testing of the tracer in larger group of patients with rheumatoid arthritis planned in the next phase of clinical trials. The effective radiation dose of ⁶⁸Ga-DOTA-Siglec-9 was within the same range as those of other ⁶⁸Ga-labeled tracers. Injection of 150 MBq of ⁶⁸Ga-DOTA-Siglec-9 would expose a subject to 3.3 mSv. These findings support the possible repeated clinical use of ⁶⁸Ga-DOTA-Siglec-9, e.g., in trials aiming to elucidate the treatment efficacy of novel drug candidates.