Rachel Bartlett

Positron Lymphography: Multimodal, High-Resolution, Dynamic Mapping and Resection of Lymph Nodes After Intradermal Injection of 18F-FDG

The lymphatic system plays a critical role in the maintenance of healthy tissues. Its function is an important indicator of the presence and extent of disease. In oncology, metastatic spread to local lymph nodes (LNs) is a strong predictor of poor outcome. Clinical methods for the visualization of LNs involve regional injection and tracking of 99mTc-sulfur colloid (99mTc-SC) along with absorbent dyes. Intraoperatively, these techniques suffer from the requirement of administration of multiple contrast media (99mTc-SC and isosulfan blue), unwieldy γ-probes, and a short effective surgical window for dyes. Preclinically, imaging of transport through the lymphatics is further hindered by the resolution of lymphoscintigraphy and SPECT. We investigated multimodal imaging in animal models using intradermal administration of 18F-FDG for combined diagnostic and intraoperative use. PET visualizes LNs with high sensitivity and resolution and low background. Cerenkov radiation (CR) from 18F-FDG was evaluated to optically guide surgical resection of LNs. Methods: Imaging of 18F-FDG uptake used PET and sensitive luminescent imaging equipment (for CR). Dynamic PET was performed in both sexes and multiple strains (NCr Nude, C57BL/6, and Nu/Nu) of mice. Biodistribution confirmed the uptake of 18F-FDG and was compared with that of 99mTc-SC. Verification of uptake and the ability to use 18F-FDG CR to guide nodal removal were confirmed histologically. Results: Intradermal injection of 18F-FDG clearly revealed lymphatic vessels and LNs by PET. Dynamic imaging revealed rapid and sustained labeling of these structures. Biodistribution of the radiotracer confirmed the active transport of radioglucose in the lymphatics to the local LNs and over time into the general circulation. 18F-FDG also enabled visualization of LNs through CR, even before surgically revealing the site, and guided LN resection. Conclusion: Intradermal 18F-FDG can enhance the preclinical investigation of the lymphatics through dynamic, high-resolution, and quantitative tomographic imaging. Clinically, combined PET/Cerenkov imaging has significant potential as a single-dose, dual-modality tracer for diagnostics (PET/CT) and guided resection of LNs (Cerenkov optical).

Image-Guided Po2 Probe Measurements Correlated with Parametric Images Derived from 18F-Fluoromisonidazole Small-Animal PET Data in Rats

18F-fluoromisonidazole PET, a noninvasive means of identifying hypoxia in tumors, has been widely applied but with mixed results, raising concerns about its accuracy. The objective of this study was to determine whether kinetic analysis of dynamic 18F-fluoromisonidazole data provides better discrimination of tumor hypoxia than methods based on a simple tissue-to-plasma ratio. Methods: Eleven Dunning R3327-AT prostate tumor-bearing nude rats were immobilized in custom-fabricated whole-body molds, injected intravenously with 18F-fluoromisonidazole, and imaged dynamically for 105 min. They were then transferred to a robotic system for image-guided measurement of intratumoral partial pressure of oxygen (Po2). The dynamic 18F-fluoromisonidazole uptake data were fitted with 2 variants of a 2-compartment, 3-rate-constant model, one constrained to have K1 equal to k2 and the other unconstrained. Parametric images of the rate constants were generated. The Po2 measurements were compared with spatially registered maps of kinetic rate constants and tumor-to-plasma ratios. Results: The constrained pharmacokinetic model variant was shown to provide fits similar to that of the unconstrained model and did not introduce significant bias in the results. The trapping rate constant, k3, of the constrained model provided a better discrimination of low Po2 than the tissue-to-plasma ratio or the k3 of the unconstrained model. Conclusion: The use of kinetic modeling on a voxelwise basis can identify tumor hypoxia with improved accuracy over simple tumor-to-plasma ratios. An effective means of controlling noise in the trapping rate constant, k3, without introducing significant bias, is to constrain K1 equal to k2 during the fitting process.

Paraquat is excluded by the blood brain barrier in rhesus macaque: An in vivo pet study

Environmental factors have long been thought to have a role in the etiology of idiopathic Parkinsons disease (PD). Since the discovery of the selective neurotoxicity of MPTP to dopamine cells, suspicion has focused on paraquat, a common herbicide with chemical structure similar to 1-methyl-4-phenylpyridinium (MPP+), the MPTP metabolite responsible for its neurotoxicity. Although in vitro evidence for paraquat neurotoxicity to dopamine cells is well established, its in vivo effects have been ambiguous because paraquat is di-cationic in plasma, which raises questions about its ability to cross the blood brain barrier. This study assessed the brain uptake of [(11)C]-paraquat in adult male rhesus macaques using quantitative PET imaging. Results showed minimal uptake of [(11)C]-paraquat in the macaque brain. The highest concentrations of paraquat were seen in the pineal gland and the lateral ventricles. Global brain concentrations including those in known dopamine areas were consistent with the blood volume in those structures. This acute exposure study found that paraquat is excluded from the brain by the blood brain barrier and thus does not readily support the causative role of paraquat exposure in idiopathic Parkinsons disease.

Fetal Dose Estimates for 18F-Fluoro-l-Thymidine Using a Pregnant Monkey Model

Estimating the radiation dose received by the fetus from nuclear medicine procedures is important because of the greater sensitivity of rapidly developing fetal tissues to ionizing radiation. 18F-fluoro-l-thymidine (FLT) uptake is related to cellular proliferation and is currently used to monitor tumor progression and response to therapy. This study was undertaken to estimate—on the basis of biodistribution data obtained by PET/CT in pregnant rhesus monkeys—radiation absorbed dose to a human fetus administered 18F-FLT. Methods: Three pregnant rhesus macaques (gestational age, 113 ± 8 d) were administered 18F-FLT and imaged for 2 h on a PET/CT scanner. Time–activity curves for maternal and fetal organs were generated in anatomic regions of interest identified via CT. Doses were estimated using OLINDA/EXM and the 6-mo-pregnant human model. Results: The extrapolated whole-body maternal dose obtained, 11.4 μGy/MBq, is similar to the previously reported adult female dose of 15.6 μGy/MBq. The estimated total-body dose to a human fetus is 24 μGy/MBq. Significant long-term 18F-FLT accumulation in fetal liver resulted in a fetal liver dose of 53 μGy/MBq. Conclusion: The fetal dose estimate in a 6-mo-pregnant human using 18F-FLT is slightly greater than that reported for 18F-FDG. 18F-FLT trapping in the fetal liver should be considered in the risk–benefit analysis of 18F-FLT PET examination in pregnant patients.

Assessment of Fetal Brain Uptake of Paraquat In Utero Using In Vivo PET/CT Imaging

Prenatal in utero conditions are thought to play a role in the development of adult diseases including Parkinsons disease (PD). Paraquat is a common herbicide with chemical structure similar to 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine, a neurotoxin known to induce parkinsonism. In order to assess the role of in utero paraquat exposure in PD, uptake in maternal and fetal brains were measured using positron emission tomography (PET)/computed tomography (CT) imaging. Two anesthetized pregnant rhesus macaques in the late second trimester of pregnancy were given bolus iv injections of ¹¹C-paraquat, and whole-body PET/CT imaging was performed. Using maternal ventricular blood pool as the input function, the unidirectional influx rate constants (K(i)s), a measure of the irreversible transport of paraquat from plasma to brain, were calculated for the maternal and fetal brains using Patlak graphical analysis. Results indicate minimal uptake of paraquat by both maternal and fetal brains with average K(i)s of 0.0009 and 0.0016 per minute, respectively. The highest regional cerebral uptake in the maternal brain (0.0009% injected dose) was seen in the pineal gland, a structure known to lack a blood brain barrier. The finding of minimal paraquat uptake in maternal and fetal brains is similar to previous findings in adult male macaques and extends the contention that a single acute paraquat exposure, prenatally or postnatally, is unlikely to play a role in PD.

Quantitative graphical analysis of simultaneous dynamic PET/MRI for assessment of prostate cancer.

Purpose Dynamic FDG imaging for prostate cancer characterization is limited by generally small size and low uptake in prostate tumors. Our aim in this pilot study was to explore feasibility of simultaneous PET/MRI to guide localization of prostate lesions for dynamic FDG analysis using a graphical approach. Methods Three patients with biopsy-proven prostate cancer underwent simultaneous FDG PET/MRI, incorporating dynamic prostate imaging. Histology and multiparametric MRI findings were used to localize tumors, which in turn guided identification of tumors on FDG images. Regions of interest were manually placed on tumor and benign prostate tissue. Blood activity was extracted from a region of interest placed on the femoral artery on PET images. FDG data were analyzed by graphical analysis using the influx constant Ki (Patlak analysis) when FDG binding seemed irreversible and distribution volume VT (reversible graphical analysis) when FDG binding seemed reversible given the presence of washout. Results Given inherent coregistration, simultaneous acquisition facilitated use of MRI data to localize small lesions on PET and subsequent graphical analysis in all cases. In 2 cases with irreversible binding, tumor had higher Ki than benign using Patlak analysis (0.023 vs 0.006 and 0.019 vs 0.008 mL/cm3 per minute). In 1 case appearing reversible, tumor had higher VT than benign using reversible graphical analysis (0.68 vs 0.52 mL/cm3). Conclusions Simultaneous PET/MRI allows localization of small prostate tumors for dynamic PET analysis. By taking advantage of inclusion of the femoral arteries in the FOV, we applied advanced PET data analysis methods beyond conventional static measures and without blood sampling.

Fetal Dopamine Receptor Characteristics Assessed in Utero

Any tracer in fetal tissue comes from maternal arterial blood. Provided steady state is achieved and intermediate compartments are reversible, the Logan graphical methods should be applicable to the assessment of binding parameters in the fetal brain. Two pregnant rhesus macaques were studied with fallypride and the Logan method was used to assess dopamine receptor distribution volume ratios (DVRs) in both maternal and fetal striatum. The agreement between fetal striatal DVRs using maternal arterial blood and maternal and fetal cerebellum as input functions strongly supports our hypothesis that the conditions necessary for graphical analysis have been met.

Aromatic l-amino acid decarboxylase turnover in vivo in rhesus macaque striatum: A microPET study

The aromatic L-amino acid decarboxylase (AAAD) is involved in the de novo synthesis of dopamine, a neurotransmitter crucial in cognitive, neurobehavioral and motor functions. The goal of this study was to assess the in vivo turnover rate of AAAD enzyme protein in the rhesus macaque striatum by monitoring, using microPET imaging with the tracer [(18)F]fluoro-m-tyrosine (FMT), the recovery of enzyme activity after suicide inhibition. Results showed the AAAD turnover half-life to be about 86 h while total recovery was estimated to be 16 days after complete inhibition. Despite this relatively slow AAAD recovery, the animals displayed normal movement and behavior within 24 h. Based on the PET results, at 24 h, the animals have recovered about 20% of normal AAAD function. These findings show that normal movement and behavior do not depend on complete recovery of AAAD function but likely on pre-synaptic and post-synaptic compensatory mechanisms.