RESUMO
Pretargeting is a powerful nuclear imaging strategy to achieve enhanced imaging contrast for nanomedicines and reduce the radiation burden to healthy tissue. Pretargeting is based on bioorthogonal chemistry. The most attractive reaction for this purpose is currently the tetrazine ligation, which occurs between trans-cyclooctene (TCO) tags and tetrazines (Tzs). Pretargeted imaging beyond the blood-brain barrier (BBB) is challenging and has not been reported thus far. In this study, we developed Tz imaging agents that are capable of ligating in vivo to targets beyond the BBB. We chose to develop 18F-labeled Tzs as they can be applied to positron emission tomography (PET) - the most powerful molecular imaging technology. Fluorine-18 is an ideal radionuclide for PET due to its almost ideal decay properties. As a non-metal radionuclide, fluorine-18 also allows for development of Tzs with physicochemical properties enabling passive brain diffusion. To develop these imaging agents, we applied a rational drug design approach. This approach was based on estimated and experimentally determined parameters such as the BBB score, pretargeted autoradiography contrast, in vivo brain influx and washout as well as on peripheral metabolism profiles. From 18 initially developed structures, five Tzs were selected to be tested for their in vivo click performance. Whereas all selected structures clicked in vivo to TCO-polymer deposited into the brain, [18F]18 displayed the most favorable characteristics with respect to brain pretargeting. [18F]18 is our lead compound for future pretargeted neuroimaging studies based on BBB-penetrant monoclonal antibodies. Pretargeting beyond the BBB will allow us to image targets in the brain that are currently not imageable, such as soluble oligomers of neurodegeneration biomarker proteins. Imaging of such currently non-imageable targets will allow early diagnosis and personalized treatment monitoring. This in turn will accelerate drug development and greatly benefit patient care.
RESUMO
Parkinson's disease (PD) is a neurodegenerative disorder that affects millions of people worldwide. Two hallmarks of PD are the accumulation of alpha-synuclein and the loss of dopaminergic neurons in the brain. There is no cure for PD, and all existing treatments focus on alleviating the symptoms. PD diagnosis is also based on the symptoms, such as abnormalities of movement, mood, and cognition observed in the patients. Molecular imaging methods such as magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET) can detect objective alterations in the neurochemical machinery of the brain and help diagnose and study neurodegenerative diseases. This review addresses the application of functional MRI, PET, and SPECT in PD patients. We provide an overview of the imaging targets, discuss the rationale behind target selection, the agents (tracers) with which the imaging can be performed, and the main findings regarding each target's state in PD. Molecular imaging has proven itself effective in supporting clinical diagnosis of PD and has helped reveal that PD is a heterogeneous disorder, which has important implications for the development of future therapies. However, the application of molecular imaging for early diagnosis of PD or for differentiation between PD and atypical parkinsonisms has remained challenging. The final section of the review is dedicated to new imaging targets with which one can detect the PD-related pathological changes upstream from dopaminergic degeneration. The foremost of those targets is alpha-synuclein. We discuss the progress of tracer development achieved so far and challenges on the path toward alpha-synuclein imaging in humans.
