First-in-human study of 99mTc-labeled fucoidan, a SPECT tracer targeting P-selectin

Abstract

Background: Activation of endothelial cells and platelets in atherothrombosis is characterized by upregulation of P-selectin. As a consequence, P-selectin represents a potential target for molecular imaging to identify thrombosis at an early stage. Fucoidan is a polysaccharide ligand extracted from brown algae with nanomolar affinity for P-selectin. This first-in-human study evaluated in healthy volunteers the safety, whole-body biodistribution, and dosimetry of ^99mTc-fucoidan (Good Manufacturing Practices grade). We also investigated whether we could observe binding of ^99mTc-fucoidan to human thrombi ex vivo and in vivo. In ten healthy volunteers, conjugate whole-body scans were performed up to 24 h following intravenous injection of ^99mTc-fucoidan (370 MBq). Moreover, ^99mTc-fucoidan uptake in ex vivo human thrombi (n = 11) was measured by gamma counting. Additionally, three patients with a newly diagnosed deep vein thrombosis (DVT) were subjected to ^99mTc-fucoidan SPECT/CT imaging.

Results: ^99mTc-fucoidan was well tolerated in all participants without any drug-related adverse events. The total-body absorbed dose in males was comparable to females (0.012 ± 0.004 vs. 0.011 ± 0.005 mSv/MBq; p = 0.97). Gamma counting experiments demonstrated binding of tracer to ex vivo human thrombi that was 16% lower after blocking with a natural P-selectin ligand, Sialyl Lewis X. ^99mTc-fucoidan demonstrated specific uptake at the thrombus site in one out of three scanned patients with DVT.

Conclusions: ^99mTc-Fucoidan has a favorable biodistribution and safety profile. ^99mTc-fucoidan exhibited specific binding to human thrombi in both in vivo and ex vivo settings. Nonetheless, the in vivo results do not support further clinical investigation of ^99mTc-fucoidan as an imaging modality for DVT. Other clinical implementations of a technetium- 99m-labeled P-selectin tracer should be considered.

Trial registration: Clinicaltrials,NCT03422055.Registered 01/15/2018. URL: https://clinicaltrials.gov/study/NCT03422055 Landelijk Trial Register, NL7739. Registered 4/2/2019 . https://onderzoekmetmensen.nl/en/trial/26785.

Keywords: Dosimetry; Fucoidan; P-selectin; SPECT; Thrombus.

Fig. 1

Whole body scintigraphy and SPECT (A) Representative whole body anterior planar scintigraphy of ^99mTc-fucoidan administered to a healthy volunteer. A reference standard was placed between the legs. Planar images are through 24 h. The scale bar is measured in absolute counts. (B) SPECT images of the thorax and abdomen at 2 h after injection. Liver, spleen and kidneys are visible on a maximum intensity projection of frontal plane view (left panel), with the green line indicating the position of the corresponding axial slice (right panel)

Fig. 2

Biodistribution of ^99mTc-fucoidan Time activity curves of (A) total body, liver and (B) other organs as determined using planar scintigraphy. (C) Radioactivity in whole blood and plasma samples were measured using a well counter and decay-corrected for the time of injection. (D) Urine samples were measured and corrected for total volume of urine collected and duration of time intervals

Fig. 3

Ex vivo ^99mTc-fucoidan binding in human thrombi Binding of ^99mTc-fucoidan to human thrombi ex vivo, with and without blocking agent Sialyl Lewis X. ^99mTc-Fu indicates ⁹⁹Tc-labeled fucoidan; and SLeX, Sialyl Lewis X

Fig. 4

Focal uptake of ^99mTc-fucoidan in deep vein thrombosis of the left popliteal vein ^99mTc-fucoidan SPECT/CT image of a 50-year-old woman recently diagnosed with a deep vein thrombosis of the left popliteal vein. Focal uptake can be observed at the thrombus site. The scale bar is measured in absolute counts