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

Abstract

Sialic acid-binding immunoglubulinlike lectin 9 (Siglec-9) is a ligand of vascular adhesion protein 1. A 68Ga-labeled peptide of Siglec-9, 68Ga-DOTA-Siglec-9, holds promise as a novel PET tracer for imaging of inflammation. This first-in-humans study investigated the safety, tolerability, biodistribution, and radiation dosimetry of this radiopharmaceutical. Methods: Six healthy men underwent dynamic whole-body PET/CT. Serial venous blood samples were drawn from 1 to 240 min after intravenous injection of 162 ± 4 MBq of 68Ga-DOTA-Siglec-9. In addition to γ-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 software, version 2.2. 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. Results:68Ga-DOTA-Siglec-9 was well tolerated by all subjects. 68Ga-DOTA-Siglec-9 was rapidly cleared from the 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 comparable to 18F-FDG in detecting arthritis. Conclusion: Intravenous injection of 68Ga-DOTA-Siglec-9 was safe and biodistribution was favorable for testing of the tracer in larger group of patients with rheumatoid arthritis, as is planned for the next phase of clinical trials. The effective radiation dose of 68Ga-DOTA-Siglec-9 was within the same range as the effective radiation doses 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, such as in trials to elucidate the treatment efficacy of novel drug candidates.

• Authors: Riikka Viitanen, Olli Moisio, Petteri Lankinen, Xiang-Guo Li, Mikko Koivumäki, Sami Suilamo, Tuula Tolvanen, Kirsi Taimen, Markku Mali, Ia Kohonen, Ilpo Koskivirta, Vesa Oikonen, Helena Virtanen, Kristiina Santalahti, Anu Autio, Antti Saraste, Laura Pirilä, Pirjo Nuutila, Juhani Knuuti, Sirpa Jalkanen, Anne Roivainen
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 62 Issue 4 Pg. 577-583 (04 2021) ISSN: 1535-5667 [Electronic] United States
• PMID: 32817143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by the Society of Nuclear Medicine and Molecular Imaging.

Chemical References

• Antigens, CD
• Cell Adhesion Molecules
• Gallium Radioisotopes
• Heterocyclic Compounds, 1-Ring
• Ligands
• Radiopharmaceuticals
• SIGLEC9 protein, human
• Sialic Acid Binding Immunoglobulin-like Lectins
• 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid
• Gallium-68
• AOC3 protein, human
• Amine Oxidase (Copper-Containing)

Topics

• Adult
• Amine Oxidase (Copper-Containing) (metabolism)
• Antigens, CD (chemistry)
• Cell Adhesion Molecules (metabolism)
• Female
• Gallium Radioisotopes (chemistry)
• Heterocyclic Compounds, 1-Ring (chemistry)
• Humans
• Ligands
• Male
• Positron Emission Tomography Computed Tomography
• Radiopharmaceuticals (adverse effects, chemistry, metabolism, pharmacokinetics)
• Safety
• Sialic Acid Binding Immunoglobulin-like Lectins (chemistry)
• Solubility
• Tissue Distribution