First-in-Human Trial of Dasatinib-Derivative Tracer for Tumor Kinase-Targeted Positron Emission Tomography.

We developed a first-of-kind dasatinib-derivative imaging agent, (18)F-SKI-249380 ((18)F-SKI), and validated its use for noninvasive in vivo tyrosine kinase-targeted tumor detection in preclinical models. In this study, we assess the feasibility of using (18)F-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 post-injection of (18)F-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 post-injection and blood-based radioactivity measurements to determine the time course of tracer distribution and facilitate radiation dose estimates. A subset of three 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 (18)F-SKI. A total of 27 tumor lesions were analyzed with median SUVpeak 1.4 (range, 0.7-2.3) and tumor-to-blood ratios of 1.6 (range, 0.8-2.5) at 90 min post-injection. Intratumoral drug concentrations calculated for four reference lesions ranged from 0.03-0.07 nM. In all reference lesions, constant tracer accumulation was observed between 30-90 min post-injection. Blood radio-assay 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 plateau (n = 2). Like dasatinib, (18)F-SKI underwent extensive metabolism post-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 (SD 0.0034) mSv/MBq. Conclusion: (18)F-SKI demonstrated significant tumor uptake, distinct image contrast despite low injected doses, and rapid clearance from blood.