A Novel Technique for Performing Simultaneous Dual Radiotracer Imaging Studies in PET:A Proof of Principle Using18FMISO and18FLT

• Published in: The Journal of nuclear medicine (1978) Vol. 60
• Main Authors: Schwartz, Jazmin, Zanzonico, Pat, Longo, Valerie, Veach, Darren, Nehmeh, Sadek, Humm, John
• Format: Journal Article
• Language: English
• Published: New York Society of Nuclear Medicine 01-05-2019
• Subjects: Animal models; Aorta; Blood; Column chromatography; Compressed air; Fluorine isotopes; Hypoxia; Image acquisition; Injection; Isoflurane; Mathematical analysis; Matrix methods; Medical imaging; Motion effects; Positron emission; Positron emission tomography; Prostate; Prostate cancer; Radioactive tracers; Rate constants; Tissues; Tomography; Trapping; Tumors; Xenografts; Xenotransplantation
• ISSN: 0161-5505; 1535-5667

Objectives: Simultaneous 18FMISO and 18FLT image acquisition would allow the generation of image maps corresponding to tumor hypoxia and proliferation that are (1) automatically registered temporally and spatially, (2) avoid ambiguities associated with images acquired at different times, and (3) avoid significant short-term changes in animal and tumor physiology. The objective of this work is twofold. First, to demonstrate that simultaneous dual 18F-radiotracer imaging using 18FMISO and 18FLT is feasible in a murine model of prostate cancer. Secondly, to show via mathematical (i.e., compartmental) analysis (CA) of dynamic PET (dPET) images (rather than single-time point static) can be used to resolve the total PET imaging signal into the distinct FMISO and by FLT components images, a novel refinement of PET CA. Methods: Nine nude rats bearing subcutaneous rat prostate tumor model R3327-AT xenografts in the hind limb (minimizing respiration and motion effects) were included in this study. The rats were anesthetized with 1.5% isoflurane/compressed air and injected via tail vein with ~0.6 mCi 18FMISO. dPET MicroPET image acquisition, using Focus 120 microPET (Siemens Medical Systems), started simultaneously with 18FMISO injection. Subjects were subsequently injected with ~0.6 mCi 18FLT 40min post-FMISO injection. Venous blood samples were drawn immediately before 18FLT and 90min post-FMISO injections respectively (thus with both radiotracers present in the blood). dPET data were reconstructed into 128x128x96 matrices for each of 37 time bins (20 x15 sec + 35x300 sec), and corrected for randoms and scatter (voxel size 0.87 x 0.87 x 0.80 mm3). A first input function (IF1) for t&lt40min, i.e. when only 18FMISO was present, was deduced from the hottest 20 aortic voxels. Target volumes were drawn over the tumors and corresponding FMISO output function (OF1) time-activity curve were deduced. A 3-compartment 2-tissue (k4=0) model was used to determine the corresponding kinetic rate constants (KRCs) for 18FMISO. These KRCs and IF1 were used to model OF1 over the full acquisition (90min). The modeled18FMISO OF1 for 40-90min was then subtracted from the measured combined 18FMISO/18FLT (40-90min) TAC to extract the 18FLT OF2 and IF2a. FLT metabolite fraction was determined from each 90 min blood sample by Sep-Pak column chromatography to obtain the corrected FLT IF2. CA was then performed for 18FLT using the same model as for 18FMISO but with k4≠0, using IF2 and OF2, and 18FLT KRCs were deduced. Results: The figure shows extracted FMISO/FLT OFs and best fit (black and red squares, respectively) for (1) a&b normal tissue and (2) c&d tumor. CA showed: (1) for normal tissue, as expected, non-significant 18FMISO trapping (k3~0) and k1=k2, but significant 18FLT retention (k3~0.0004 min-1) and (2) for tumor trapping is mainly due to 18FMISO (k3~0.0004 min-1) and little 18FLT (k3~0.00008 min-1). Conclusions: To our knowledge, this is the first example of the kinetic PET analysis of serially injected, co-localizing 18F tracers that report two orthogonal molecular imaging paradigms simultaneously (hypoxia and proliferation) in a single imaging session. This work demonstrates a novel technique that could dramatically enhance the clinical use of FMISO and FLT and other potentially useful PET radiotracer combinations.