First-in-humans trial of dasatinib-derivative tracer for tumor kinase-targeted PET Journal Article
| Authors: | Krebs, S.; Veach, D. R.; Carter, L. M.; Grkovski, M.; Fornier, M.; Mauro, M. J.; Voss, M. H.; Danila, D. C.; Burnazi, E.; Null, M.; Staton, K.; Pressl, C.; Beattie, B. J.; Zanzonico, P.; Weber, W. A.; Lyashchenko, S. K.; Lewis, J. S.; Larson, S. M.; Dunphy, M. P. S. |
| Article Title: | First-in-humans trial of dasatinib-derivative tracer for tumor kinase-targeted PET |
| Abstract: | We developed a first-of-kind dasatinib-derivative imaging agent, 18F-SKI-249380 (18F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assessed the feasibility of using 18F-SKI for PET imaging in patients with malignancies. Methods: Five patients with a prior diagnosis of breast cancer, renal cell cancer, or leukemia underwent whole-body PET/CT imaging 90 min after injection of 18F-SKI (mean, 241.24 ± 116.36 MBq) as part of a prospective study. In addition, patients underwent either a 30-min dynamic scan of the upper abdomen including, at least partly, cardiac left ventricle, liver, spleen, and kidney (n = 2) or three 10-min whole-body PET/CT scans (n = 3) immediately after injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of 3 patients had a delayed whole-body PET/CT scan at 180 min. Biodistribution, dosimetry, and tumor uptake were quantified. Absorbed doses were calculated using OLINDA/EXM 1.0. Results: No adverse events occurred after injection of 18F-SKI. In total, 27 tumor lesions were analyzed, with a median SUVpeak of 1.4 (range, 0.7-2.3) and tumor-to-blood ratios of 1.6 (range, 0.8-2.5) at 90 min after injection. The intratumoral drug concentrations calculated for 4 reference lesions ranged from 0.03 to 0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30 and 90 min after injection. A blood radioassay indicated that radiotracer clearance from blood and plasma was initially rapid (blood half-time, 1.31 ± 0.81 min; plasma, 1.07 ± 0.66 min; n = 4), followed variably by either a prolonged terminal phase (blood half-time, 285 ± 148.49 min; plasma, 240 ± 84.85 min; n = 2) or a small rise to a plateau (n = 2). Like dasatinib, 18F-SKI underwent extensive metabolism after administration, as evidenced by metabolite analysis. Radioactivity was predominantly cleared via the hepatobiliary route. The highest absorbed dose estimates (mGy/MBq) in normal tissues were to the right colon (0.167 ± 0.04) and small intestine (0.153 ± 0.03). The effective dose was 0.0258 mSv/MBq (SD, 0.0034 mSv/MBq). Conclusion:18F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood. © 2020 by the Society of Nuclear Medicine and Molecular Imaging. |
| Keywords: | dasatinib; pet imaging; src kinase; 18f-ski-249380 |
| Journal Title: | Journal of Nuclear Medicine |
| Volume: | 61 |
| Issue: | 11 |
| ISSN: | 0161-5505 |
| Publisher: | Society of Nuclear Medicine |
| Date Published: | 2020-11-01 |
| Start Page: | 1580 |
| End Page: | 1587 |
| Language: | English |
| DOI: | 10.2967/jnumed.119.234864 |
| PUBMED: | 32169913 |
| PROVIDER: | scopus |
| PMCID: | PMC8524123 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 December 2020 -- Source: Scopus |
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