ABSTRACT
Oxygen-15 (ß+, t1/2 = 122 s) radiolabeled diatomic oxygen, in conjunction with positron emission tomography, is the gold standard to quantitatively measure the metabolic rate of oxygen consumption in the living human brain. We present herein a protocol for safe and effective delivery of [15O]O2 over 200 m to a human subject for inhalation. A frugal quality control testing procedure was devised and validated. This protocol can act as a blueprint for other sites seeking to implement similar imaging programs.
ABSTRACT
The gold standard for imaging the cerebral metabolic rate of oxygen (CMRO2) is positron emission tomography (PET); however, it is an invasive and complex procedure that also requires correction for recirculating 15O-H2O and the blood-borne activity. We propose a noninvasive reference-based hybrid PET/magnetic resonance imaging (MRI) method that uses functional MRI techniques to calibrate 15O-O2-PET data. Here, PET/MR imaging of oxidative metabolism (PMROx) was validated in an animal model by comparison to PET-alone measurements. Additionally, we investigated if the MRI-perfusion technique arterial spin labelling (ASL) could be used to further simplify PMROx by replacing 15O-H2O-PET, and if the PMROx was sensitive to anesthetics-induced changes in metabolism. Methods: 15O-H2O and 15O-O2 PET data were acquired in a hybrid PET/MR scanner (3 T Siemens Biograph mMR), together with simultaneous functional MRI (OxFlow and ASL), from juvenile pigs (n = 9). Animals were anesthetized with 3% isoflurane and 6 mL/kg/h propofol for the validation experiments and arterial sampling was performed for PET-alone measurements. PMROx estimates were obtained using whole-brain (WB) CMRO2 from OxFlow and local cerebral blood flow (CBF) from either noninvasive 15O-H2O-PET or ASL (PMROxASL). Changes in metabolism were investigated by increasing the propofol infusion to 20 mL/kg/h. Results: Good agreement and correlation were observed between regional CMRO2 measurements from PMROx and PET-alone. No significant differences were found between OxFlow and PET-only measurements of WB oxygen extraction fraction (0.30 ± 0.09 and 0.31 ± 0.09) and CBF (54.1 ± 16.7 and 56.6 ± 21.0 mL/100 g/min), or between PMROx and PET-only CMRO2 estimates (1.89 ± 0.16 and 1.81 ± 0.10 mLO2/100 g/min). Moreover, PMROx and PMROxASL were sensitive to propofol-induced reduction in CMRO2 Conclusion: This study provides initial validation of a noninvasive PET/MRI technique that circumvents many of the complexities of PET CMRO2 imaging. PMROx does not require arterial sampling and has the potential to reduce PET imaging to 15O-O2 only; however, future validation involving human participants are required.
ABSTRACT
INTRODUCTION: Oxygen-15 (O; t½ = 122.4 s) has been used for nuclear imaging experiments since the beginning of the field. With the advent of simultaneous hybrid PET/MR technology, [O]water has seen a resurgence and remains the gold standard method for quantitative blood flow studies. The short half-life presents a nontrivial challenge to applying current good manufacturing practices production methods to maintain patient safety. METHODS: A two-vial production method was devised to ensure adequate mixing of [O]water vapour into buffered isotonic saline. For production validation, six batches of [O]water were prepared: sterility, quality control testing and four patient doses. The final dose also underwent quality tested. Routine quality control testing included the following: radiochemical identity and purity, radionuclidic identity and purity, appearance, pH, pyrogenicity, and filter integrity. Sterility was retrospectively confirmed. For validation, breakthrough Pt concentration was also measured. RESULTS: Consistent yields of 10-12 GBq (270-325 mCi) were obtained 3 min after bombardment. Overall, 26 [O]water batches underwent quality control testing under this protocol and all met or exceeded release specifications for clinical use. CONCLUSION: The multiple batch protocol proved to be a safe and effective means for producing [O]water. Furthermore, this protocol could be readily adapted by any facility attempting to produce [O]water for clinical studies. Compared with previous attempts at our site, the protocol outlined here was more consistent and reliable, improved production workflow and led to more available radioactivity for participant injection and QC testing.
