V-48 labeled VO(acac)2for hybrid PET/MR imaging of cancer

1176 Objectives: We previously demonstrated the use of vanadyl (VO2+) chelate bis(acetylacetonato) oxovanadium(IV) [VO(acac)2] as an effective contrast agent in magnetic resonance imaging (MRI) for potential early detection and staging of cancer, such as in mouse models of colorectal cancer (CRC) [1,2]. Previous studies showed increased tumor uptake of 48V-VO(acac)2 in PET (positron emission tomography) imaging in CRC [3]. Our current research is extended to development of dual-modality PET/MR imaging using 48V labeled VO(acac)2 for improved imaging in cancer detection and staging. We report our progress on improving the cyclotron production of 48V, optimizing the synthesis of 48V-VO(acac)2, decreasing radiotracer impurities, and validating the utility of this new radiotracer in PET/MR studies of CRC in mouse models. Methods: Two thin natural titanium foils were irradiated via the 48Ti(p,n)48V reaction at 40 µA until an optimal activity was obtained. The foil was left to decay overnight to mitigate short-lived isotopes. The target was dissolved in HF and H2SO4 (4:1) and 48V was isolated in a series of radiochemical steps before being complexed with acetyl acetone under reflux to form 48V-VO(acac)2. The solution was passed through an OnGuard II M cartridge (Thermo Fisher Scientific), used to concentrate free transition metals, to separate 48V-VO(acac)2 from free vanadium, which does not target the same metabolic pathways and decreases image quality. The purity of the resulting radiotracer was assessed using aluminum-backed thin layer chromatography (TLC). Two drops of the sample were placed 1 cm from the plate edge. The plate was developed in MeOH and H2O (99:1) and evaluated using a TLC imaging scanner (Mini-Scan, Eckert & Ziegler): chelated and free vanadium were expected to separate due to their chemical state. Once purity was established, the radiotracer was validated in PET/MR studies by demonstrating uptake in a xenograph mouse model of CRC. Mice were imaged over 30 minutes in an MRI scanner with a PET-insert. The results were confirmed with separate PET and MR imaging studies. In-vivo biodistribution studies were performed 48 hours post injection. Results: Two thin 12 µm natural titanium foils (13 mg together) were irradiated for 33 hours amounting to 1323µA[asterisk]h, yielding 17.8 mCi which decayed to 11.65 mCi by the beginning of isolation. Both foils were dissolved in 400 µL HF and 100 µL H2SO4. After heating under argon flow, 10.6 mCi were transferred to a platinum crucible, neutralized, and oxidized at 790°C with a mixture of Na2CO3 and NaNO3 (43:1). Once cooled, 7.5 mCi were centrifuged for 10 minutes at 5000 rpm. The 7 mCi supernatant was pH adjusted to 3-4 with HCl. The solution was passed through a Chelex-100 column which was then eluted with NH3, yielding 3.8 mCi as NH4VO3. The solvent was dried at 300°C before 1.3 mCi was combined with acetyl acetonate and heated under reflux. The resulting 182 µCi of 48V-VO(acac)2 was passed through an OnGuard II M filter, which trapped free vanadium and passed 48V-VO(acac)2, yielding 85 µCi. The composition of the eluent was assessed twice with TLC, showing high counts of 48V-VO(acac)2. Uptake of 48V-VO(acac)2 was validated in PET/MR imaging experiments. The biodistribution was followed two days post injection and confirmed the uptake of the radiotracer in respective organs and tumor. Conclusion: This experiment yielded a workable geometry for foil irradiation given the activity produced. Despite low synthesis yields, several steps were identified for improvement. Further investigation found that additional steps should be taken when chelated compounds are present using the OnGuard II M cartridge; forgoing these steps results in a smearing of yellow iron in the cartridge, which was observed. The counts of free vanadium indicate the filtration was not completely successful; the additional procedure could produce higher yields. PET/MR imaging validated the increased uptake of this novel radiotracer for potentially improving early cancer detection.