The process to develop and evaluate fluorine 18 fluorthanatrace as a PET radiotracer for cancer imaging requires substantial time and resources, but it may improve the diagnosis and clinical manage... Fluorine 18 (18F) fluorthanatrace (18F-FTT) is a PET radiotracer for imaging poly (adenosine diphosphate–ribose) polymerase-1 (PARP-1), an important target for a class of drugs known as PARP inhibi...

Resistance to chemotherapy is an important challenge in the clinical management of triple-negative breast cancer (TNBC). Utilization of the amino acid glutamine as a key nutrient is a metabolic signature of TNBC featuring high glutaminase (GLS) activity and a large pool of cellular glutamate, which mediates intracellular enrichment of cystine via xCT (SLC7A11) antiporter activity. To overcome chemo-resistant TNBC, we identified a strategy of dual metabolic inhibition of GLS and xCT to sensitize resistant TNBC cells to chemotherapy. We successfully tested this strategy in a human TNBC line and its chemoresistant variant in vitro and their xenograft models in vivo. Key findings of our study include: 1. Dual metabolic inhibition induced pronounced reductions of cellular glutathione accompanying significant increases of cellular superoxide level in both parent and resistant TNBC cells. While GLS and xCT inhibition did not directly kill cells via apoptosis, they potentiated doxorubicin (DOX) and cisplatin (CIS) to induce remarkably higher levels of apoptosis than DOX or CIS alone. 2. Although the resistant TNBC cells exhibited higher capacity to mitigate oxidative stress than the parent cells, their resistance was overcome by dual metabolic inhibition combined with DOX or CIS. 3. In vivo efficacy and safety of the triple combination (GLS and xCT inhibition plus DOX or CIS) were demonstrated in both chemo sensitive and resistant TNBC tumors in mice. In conclusion, GLS and xCT inhibition resulted in unmitigated oxidative stress due to depletion of glutathione, representing a promising strategy to overcome chemoresistance in glutamine-dependent TNBC.

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.

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.

A novel brain positron emission tomography (PET) radioligand, [¹¹C]HY-2-15, has potential for imaging alpha-synuclein aggregations in multiple system atrophy and misfolded tau proteins in tauopathies, based on its high binding affinity in disease brain tissue homogenates. Here, we demonstrate that [³H]HY-2-15 has the capability to bind to aggregated alpha-synuclein in multiple system atrophy brain and tau aggregations in progressive supranuclear palsy and corticobasal degeneration brain tissues via in vitro autoradiography study. A first-in-human pilot multicenter clinical study recruited a total of 10 subjects including healthy controls and patients with Parkinson’s disease, multiple system atrophy, or progressive supranuclear palsy. The study revealed that [¹¹C]HY-2-15 has a relatively higher specific uptake in the pallidum and midbrain of patients with progressive supranuclear palsy. Total-body scans performed on the PennPET Explorer showed the radiotracer was cleared by renal excretion. However, the rapid metabolism and low brain uptake resulted in a limited signal of [¹¹C]HY-2-15 in brain.