Investigation of V-48 Labeled VO(acac)₂ for Cancer Imaging

Objectives: Previous research has demonstrated that vanadyl (VO²⁺) chelate bis(acetylacetonato) oxovanadium(IV) [VO(acac)₂] is an effective contrast agent for early detection of cancer using magnetic resonance imaging (MRI) [1,2], as well as for enhancing uptake of F-18 labeled deoxyglucose (FDG) in cancer imaging using positron emission tomography (PET) [3]. These two imaging utilities of VO(acac)₂ have opened avenues to develop new cancer imaging strategies for potentially improving early diagnosis. For example, in dual-modality PET/MRI scanning, V-48 labeled VO(acac)₂ [V-48-VO(acac)₂] could be used to detect early-stage cancer as a result of improved image contrast in both PET and MRI. This current research project focuses on investigation of optimal approaches for the cyclotron-based production of V-48 and efficient synthesis of V-48-VO(acac)₂, and the biodistribution of this novel radiotracer in mouse models.

Methods: Thin natural titanium foils were irradiated using a 48Ti(p,n)48V reaction within an IBA cyclotron. Variable proton currents and durations of irradiation were used to characterize the optimal time and conditions to produce the desired amount of radioactivity, initially set at 1-2 mCi. The target was then assayed to detect the amount of radiation and characteristic gamma-rays and determine the composition of the sample. The target was dissolved and purified in a series of radiochemical steps to isolate the V-48 and obtain an optimal level of purity. After radioproduction was optimized, efficient and effective synthesis methods for routinely producing V-48-VO(acac)₂ as ammonium vanadate or vanadyl acetylacetonate were developed. The resulting radiotracer was used in an imaging study of mouse model of colorectal cancer (CRC) as a proof-of-concept demonstration. Preliminary in vivo biodistribution studies were performed via microPET/CT over 48 hours post injection. Results: The titanium foils were irradiated at times varying from 30 minutes to a total of 20 hours and at currents from 10 μA to 40 μA; for example, for a current of 20 μA, 20 hours of irradiation produced the desired radiation yield (1.1 mCi), and 10 hours at 40 μA produced twice the desired yield (2.02 mCi). To extract the V-48 from the target, the target was dissolved in sulfuric acid and dropwise concentrations of hydrofluoric acid, neutralized and fused with sodium carbonate and sodium nitrate, centrifuged, pH adjusted with hydrochloric acid, and passed through a chelex column which was then eluted with ammonia. A 15 mg irradiated target typically produced a 60% yield of V-48 after decay corrections. The increased uptake of V-48-VO(acac)₂ in a CRC xenograft model was validated in PET/CT imaging experiments; the biodistribution was followed for more than 2 days after injection. These preliminary results can be utilized to design innovative PET/CT or PET/MRI imaging strategies in early detection of CRC and other cancers. Conclusion: We have successfully developed and optimized the cyclotron-based techniques for routine production of V-48, and efficient approaches to synthesize V-48-VO(acac)₂ for conducting routine animal studies. We have also validated the increased uptake of V-48-VO(acac)₂ in a CRC mouse model, and collected in vivo biodistribution data of this new PET radiotracer for designing innovative PET and PET/MRI methodologies and improve early detection of cancers.