Dosimetry of 18F-labeled tyrosine kinase inhibitor SKI-249380, a dasatinib-tracer for PET imaging

Abstract

Purpose: To obtain estimates of human normal-organ radiation doses of ¹⁸F-SKI-249380, as a prerequisite step towards first-in-human trial. ¹⁸F-SKI-249380 is a first-of-its-kind PET tracer for imaging the in vivo pharmacokinetics of dasatinib, an investigational targeted therapy for solid malignancies.

Procedures: Isoflurane-anesthetized mice received tracer dose via tail vein. Organ time-integrated activity coefficients, fractional urinary and hepatobiliary excretion, and total-body clearance kinetics were derived from PET data, with allometric extrapolation to the Standard Man anatomic model and normal-organ-absorbed dose calculations using OLINDA/EXM software.

Results: The human effective dose was 0.031 mSv/MBq. The critical organ was the upper large intestine, with a dose equivalent of 0.25 mSv/MBq. A 190-MBq administered activity of ¹⁸F-SKI-249380 is thus predicted to expose an adult human to radiation doses generally comparable to those of routinely used diagnostic radiopharmaceuticals.

Conclusions: Animal-based human dose estimates support first-in-human testing of ¹⁸F-SKI-249380.

Fig. 1

Example of animal ¹⁸F-SKI-249380 PET imagery for data analyses. In each mouse, 60 min of PET data was reconstructed and summed. Murine organs were selected for special organ-level dosimetric analysis when these demonstrated high or low activity, relative to the remainder of the body, scintigraphically; accounting for all other injected activity, including radioactive excreta, as described in “Methods”. Images: coronal (left and middle) and sagittal (right) sections illustrating, as examples, distinct levels of activity in the urinary bladder (grey arrow); renal cortex (black arrow); and brain (white arrow; i.e., distinctly low brain uptake—a “deficit” organ). The Electronic Supplementary Material (Online Resource 2) illustrates digital VOI analysis of PET imagery.

Fig. 2

Example of animal PET imaging data from one mouse. Shown are serial 1 min-duration frames, of a single coronal plane, obtained during 60 min of dynamic imaging; from left to right: 1, 2, 5, 15, 30, and 60 min, post-tracer injection. The images are scaled to the same grayscale, with black representing ≥22% injected activity/mL. The coronal sections shows the cross-hair centered on the gallbladder region; the head of the mouse is at the bottom of each frame. The images illustrate the predominant hepatobiliary excretion.

Fig. 3

Organ activity time data from animal PET imaging. Each datum shown represents the average value from ten mice studied; with error bars indicating the standard deviation. Abscissa in units of hours after tracer injection. Ordinate axis in units of % IA/mL; except for urinary bladder data plotted in units of % IA. Top left: bone; top right: cardiac blood pool; bottom left: lungs; bottom right: brain. Organ activity time data from animal PET imaging. Each datum shown represents the average value from ten mice studied; with error bars indicating the standard deviation. Abscissa in units of hours after tracer injection. Ordinate axis in units of % IA/mL; except for urinary bladder data plotted in units of % IA. Top left: liver; top right: urinary bladder (excreta); bottom left: kidneys; bottom right: muscle.