Proof-of-concept PET imaging of pulmonary sarcoidosis using VAP-1-targeted radiotracer [(68)Ga]Ga-DOTA-Siglec-9.

BACKGROUND: Sarcoidosis is a multisystem granulomatous disease of unknown etiology, with pulmonary involvement being the most common and clinically significant manifestation. Vascular adhesion protein-1 (VAP-1) plays a key role in leukocyte trafficking to inflamed tissues. [⁶⁸Ga]Ga-DOTA-Siglec-9 is a novel PET radiotracer that binds to VAP-1. This proof-of-concept study aimed to evaluate the feasibility of [(68)Ga]Ga-DOTA-Siglec-9 PET/CT for imaging pulmonary sarcoidosis. METHODS: Six patients with stage 2 pulmonary sarcoidosis (age 50.5 ± 13.1 years; bodyweight 84.2 ± 14.7 kg), diagnosed by clinical, radiological, and histological findings, underwent [(68)Ga]Ga-DOTA-Siglec-9 PET/CT. Control subjects included six healthy male volunteers (age 37.5 ± 10.3 years; bodyweight 80.3 ± 3.9 kg) and one female patient with lung cancer (age 77 years; bodyweight 62 kg). Tracer uptake was quantified in the lungs, mediastinal lymph nodes, and organs involved in systemic inflammation. RESULTS: Patients with sarcoidosis showed significantly higher [(68)Ga]Ga-DOTA-Siglec-9 uptake in the lungs (SUV(mean) 1.82 ± 0.52 vs. 0.41 ± 0.08; P = 0.00006) and mediastinal lymph nodes (SUV(mean) 2.06 ± 0.46 vs. 0.89 ± 0.26; P = 0.0003) compared to healthy controls. Increased uptake was also observed in the liver (SUV(mean) 1.18 ± 0.14 vs. 0.80 ± 0.10, P = 0.0003), spleen (SUV(mean) 1.13 ± 0.09 vs. 0.82 ± 0.06, P = 0.00003), bone marrow (SUV(mean) 0.30 ± 0.12 vs. 0.06 ± 0.05, P = 0.001), and bone (SUV(mean) 0.27 ± 0.11 vs. 0.08 ± 0.04, P = 0.004), indicating systemic inflammation. CONCLUSIONS: This proof-of-concept study demonstrates the potential of VAP-1-targeted [(68)Ga]Ga-DOTA-Siglec-9 PET/CT for imaging pulmonary sarcoidosis and associated inflammatory activity. Further validation in larger cohorts is warranted. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03755245 (registered 27 November 2018), NCT05212103 (registered 27 January 2022). GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12931-025-03455-8.