Although the precise molecular mechanisms responsible for neuronal death and motor dysfunction in late-onset Parkinson’s disease (PD) are unknown, evidence suggests that mitochondrial dysfunction and neuroinflammation occur early, leading to a collective increase in reactive oxygen species (ROS) production and oxidative stress. However, the lack of methods for tracking oxidative stress in the living brain has precluded its use as a potential biomarker. The goal of the current study is to address this need through the evaluation of the first superoxide (O₂^•−)-sensitive radioactive tracer, [¹⁸F]ROStrace, in a model of late-onset PD. To achieve this goal, MitoPark mice with a dopaminergic (DA) neuron-specific deletion of transcription factor A mitochondrial (Tfam) were imaged with [¹⁸F]ROStrace from the prodromal phase to the end-stage of PD-like disease. Our data demonstrate [¹⁸F]ROStrace was sensitive to increased oxidative stress during the early stages of PD-like pathology in MitoPark mice, which persisted throughout the disease course. Similarly to PD patients, MitoPark males had the most severe parkinsonian symptoms and metabolic impairment. [¹⁸F]ROStrace retention was also highest in MitoPark males, suggesting oxidative stress as a potential mechanism underlying the male sex bias of PD. Furthermore, [¹⁸F]ROStrace may provide a method to identify patients at risk of Parkinson’s before irreparable neurodegeneration occurs and enhance clinical trial design by identifying patients most likely to benefit from antioxidant therapies.

The synucleinopathies are a diverse group of neurodegenerative disorders characterized by the accumulation of aggregated alpha-synuclein (aSyn) in vulnerable populations of brain cells. Oxidative stress is both a cause and a consequence of aSyn aggregation in the synucleinopathies; however, noninvasive methods for detecting oxidative stress in living animals have proven elusive. In this study, we used the reactive oxygen species (ROS)-sensitive positron emission tomography (PET) radiotracer [¹⁸F]ROStrace to detect increases in oxidative stress in the widely-used A53T mouse model of synucleinopathy. A53T-specific elevations in [¹⁸F]ROStrace signal emerged at a relatively early age (6–8 months) and became more widespread within the brain over time, a pattern which paralleled the progressive development of aSyn pathology and oxidative damage in A53T brain tissue. Systemic administration of lipopolysaccharide (LPS) also caused rapid and long-lasting elevations in [¹⁸F]ROStrace signal in A53T mice, suggesting that chronic, aSyn-associated oxidative stress may render these animals more vulnerable to further inflammatory insult. Collectively, these results provide novel evidence that oxidative stress is an early and chronic process during the development of synucleinopathy and suggest that PET imaging with [¹⁸F]ROStrace holds promise as a means of detecting aSyn-associated oxidative stress noninvasively.

[18F]Fluortriopride (FTP) was developed as a dopamine D3-selective radiotracer, thought to be important to neurobiological reward pathways and implicated in drug addiction, Parkinson’s disease, and schizophrenia. Preclinical radiation dosimetry studies found the gallbladder wall received the highest dose. A gallbladder dose reduction intervention was simulated using a novel reduction model for healthy adults following fatty-meal consumption. The goals of this study were to assess whole body FTP human dosimetry and determine the feasibility of reducing absorbed dose to the gallbladder wall. Effective dose without a fatty meal was 0.022 ± 0.002 mSv/MBq (± standard deviation) with highest organ dose of 0.436 ± 0.178 mSv/MBq to the gallbladder wall (n = 10). Predicted gallbladder dose reduction with fatty meal consumed was 67.4% (n = 10). Meal consumption by four repeat volunteers decreased average gallbladder dose by 71.3% (n = 4) compared to the original ten volunteers. Observed effective doses were adequately low to continue studying FTP uptake in humans. Validated dosimetry simulations indicate up to a 71% reduction in gallbladder dose can be achieved by employing intrinsic physiology to contract the gallbladder via fatty meal ingestion. This methodology for predicting gallbladder absorbed dose reduction from fatty meal consumption can be applied to other radiopharmaceuticals and radiotherapies.

L-Glutamine (L-Gln) is the most abundant amino acid present in the human body and is involved in numerous metabolic pathways. Glutaminolysis is the metabolic process deployed by many aggressive cancers such as triple negative breast cancer (TNBC). Imaging the metabolic pathways of L-glutamine could provide more insights into tumor biology. Reliable and reproducible automated synthesis of [11C]L-glutamine PET (Positron Emission Tomography) radiotracer is critical for these studies. [11C]L-Glutamine ([11C]L-Gln) was reliably and reproducibly synthesized. The automated process involves cleaning and drying of the synthesis module, azeotropic drying of crown ether and cesium bicarbonate, conversion of [11C]CO2 to [11C] CsCN, incorporation of [11C] CN into the starting material, and hydrolysis and deprotection of the corresponding [11C] nitrile to yield [11C]L-glutamine. Starting with approximately 1 Ci of [11C] cesium cyanide ([11C]CsCN), 47–77 mCi (n = 4) of the final product, [11C]L-Gln, was obtained after sterile filtration. The radiochemical purity of the final product was > 90% with almost exclusively L-glutamine isomer. The yield of [11C]L-Gln was 43–52% (n = 4), decay corrected to end of [11C] CsCN trapping in the reaction vessel. All the steps including drying of the mixture of base and crown ether, preparation of [11C] cyanide, radiochemical synthesis and formulation were accomplished on a single synthesis unit. [11C]L-Gln has been successfully adapted and optimized on an automated synthesis module, Synthra HCN Plus. This process can be readily adapted for clinical research use.

Oxidative stress, defined as the excessive production of reactive oxygen species (ROS), is a crucial factor in the pathogenesis of various neurodegenerative diseases, including the 4-repeat (4R) tauopathies. Collectively, the 4R tauopathies are characterized by the progressive aggregation of tau protein isoforms with four microtubule-binding domains in and around brain cells. The cyclical relationship between oxidative stress and 4R tau aggregation suggests that a means of imaging ROS noninvasively could be a valuable tool for the study and treatment of 4R tauopathy in both humans and animal models. To demonstrate the potential of the ROS-sensitive positron emission tomography (PET) radiotracer [¹⁸F]ROStrace as a means of filling this methodological gap, we performed [¹⁸F]ROStrace PET imaging on PS19 mice, which exhibit 4R tau aggregation similar to that seen in human 4R tauopathy. Significant increases in [¹⁸F]ROStrace signal became detectable in the hippocampus of 6–11-month-old (mo) PS19 animals and spread to the brainstem, midbrain, and thalamus of 11+ mo animals. Additionally, older PS19 mice displayed higher whole-brain average [¹⁸F]ROStrace signal compared to age-matched controls (p = 0.042), and tau pathology consistently colocalized with multiple fluorescent indicators of oxidative stress in PS19 brain samples. These results provide novel evidence that 4R tau aggregation is associated with increased oxidative stress in PS19 mouse brain and advance [¹⁸F]ROStrace as a noninvasive technology for the detection of oxidative stress in neurodegenerative diseases involving tau pathology.