Nanomaterials offer unique physical, chemical and biological properties of interest for medical imaging and therapy. Over the last two decades, there has been an increasing effort to translate nanomaterial-based medicinal products (so-called nanomedicines) into clinical practice and, although multiple nanoparticle-based formulations are clinically available, there is still a disparity between the number of pre-clinical products and those that reach clinical approval. To facilitate the efficient clinical translation of nanomedicinal-drugs, it is important to study their whole-body biodistribution and pharmacokinetics from the early stages of their development. Integrating this knowledge with that of their therapeutic profile and/or toxicity should provide a powerful combination to efficiently inform nanomedicine trials and allow early selection of the most promising candidates. In this context, radiolabelling nanomaterials allows whole-body and non-invasive in vivo tracking by the sensitive clinical imaging techniques positron emission tomography (PET), and single photon emission computed tomography (SPECT). Furthermore, certain radionuclides with specific nuclear emissions can elicit therapeutic effects by themselves, leading to radionuclide-based therapy. To ensure robust information during the development of nanomaterials for PET/SPECT imaging and/or radionuclide therapy, selection of the most appropriate radiolabelling method and knowledge of its limitations are critical. Different radiolabelling strategies are available depending on the type of material, the radionuclide and/or the final application. In this review we describe the different radiolabelling strategies currently available, with a critical vision over their advantages and disadvantages. The final aim is to review the most relevant and up-to-date knowledge available in this field, and support the efficient clinical translation of future nanomedicinal products for in vivo imaging and/or therapy.

/pdf/radiolabelling-of-nanomaterials-for-medical-imaging-and-1wnnia4i8w.pdf

Radiolabelling of nanomaterials for medical imaging and therapy.

Recombinant viruses are the workhorse of modern neuroscience. Whether one would like to understand a neuron's morphology, natural activity patterns, molecular composition, connectivity or behavioural and physiologic function, most studies begin with the injection of an engineered virus, often an adeno-associated virus or herpes simplex virus, among many other types. Recombinant viruses currently enable some combination of cell type-specific, circuit-selective, activity-dependent and spatiotemporally resolved transgene expression. Viruses are now used routinely to study the molecular and cellular functions of a gene within an identified cell type in the brain, and enable the application of optogenetics, chemogenetics, calcium imaging and related approaches. These advantageous properties of engineered viruses thus enable characterization of neuronal function at unprecedented resolution. However, each virus has specific advantages and disadvantages, which makes viral tool selection paramount for properly designing and executing experiments within the central nervous system. In the current Review, we discuss the key principles and uses of engineered viruses and highlight innovations that are needed moving forward.

Viral tools for neuroscience.

Neuroinflammation play an important role in Alzheimer's disease pathogenesis. Advances in molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with Alzheimer's disease central pathologies in patients and in animal disease models. Recent single-cell sequencing and transcriptomics indicate dynamic disease-associated microglia and astrocyte profiles in Alzheimer's disease. Mitochondrial 18-kDa translocator protein is the most widely investigated target for neuroinflammation imaging. New generation of translocator protein tracers with improved performance have been developed and evaluated along with tau and amyloid imaging for assessing the disease progression in Alzheimer's disease continuum. Given that translocator protein is not exclusively expressed in glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 receptor, purinergic P2X7 receptor, P2Y12 receptor, the fractalkine receptor, triggering receptor expressed on myeloid cells 2, and receptor for advanced glycation end products. Promising targets should demonstrate a higher specificity for cellular locations with exclusive expression in microglia or astrocyte and activation status (pro- or anti-inflammatory) with highly specific ligand to enable in vivo brain imaging. In this review, we summarised recent advances in the development of neuroinflammation imaging tracers and provided an outlook for promising targets in the future.

/pdf/pet-imaging-of-neuroinflammation-in-alzheimer-s-disease-4fcxjv9jdz.pdf

PET Imaging of Neuroinflammation in Alzheimer's Disease.

Current progress and limitations of AAV mediated delivery of protein therapeutic genes and the importance of developing quantitative pharmacokinetic/pharmacodynamic (PK/PD) models

Following the impressive progress in the treatment of relapsing-remitting multiple sclerosis (MS), the major challenge ahead is the development of treatments to prevent or delay the irreversible accumulation of clinical disability in progressive forms of the disease. The substrate of clinical progression is neuro-axonal degeneration, and a deep understanding of the mechanisms that underlie this process is a precondition for the development of therapies for progressive MS. PET imaging involves the use of radiolabelled compounds that bind to specific cellular and metabolic targets, thereby enabling direct in vivo measurement of several pathological processes. This approach can provide key insights into the clinical relevance of these processes and their chronological sequence during the disease course. In this Review, we focus on the contribution that PET is making to our understanding of extraneuronal and intraneuronal mechanisms that are involved in the pathogenesis of irreversible neuro-axonal damage in MS. We consider the major challenges with the use of PET in MS and the steps necessary to realize clinical benefits of the technique. In addition, we discuss the potential of emerging PET tracers and future applications of existing compounds to facilitate the identification of effective neuroprotective treatments for patients with MS.

Positron emission tomography in multiple sclerosis - straight to the target.

Neuroinflammation is a key pathologic hallmark of numerous neurologic diseases, however, its exact role in vivo is yet to be fully understood PET imaging enables investigation, quantification, and tracking of different neuroinflammation biomarkers in living subjects longitudinally One such biomarker that has been imaged extensively using PET is translocator protein 18 kDa (TSPO) Although imaging TSPO has yielded valuable clinical data linking neuroinflammation to various neurodegenerative diseases, considerable limitations of TSPO PET have prompted identification of other more cell-specific and functionally relevant biomarkers This review analyzes the clinical potential of available and emerging PET biomarkers of innate and adaptive immune responses, with mention of exciting future directions for the field

https://jnm.snmjournals.org/content/jnumed/61/8/1107.full.pdf

Neuroinflammation PET Imaging: Current Opinion and Future Directions.

Adeno-associated viruses (AAVs) are typically single-stranded deoxyribonucleic acid (ssDNA) encapsulated within 25-nm protein capsids. Recently, tissue-specific AAV capsids (e.g. PHP.eB) have been shown to enhance brain delivery in rodents via the LY6A receptor on brain endothelial cells. Here, we create a non-invasive positron emission tomography (PET) methodology to track viruses. To provide the sensitivity required to track AAVs injected at picomolar levels, a unique multichelator construct labeled with a positron emitter (Cu-64, t1/2 = 12.7 h) is coupled to the viral capsid. We find that brain accumulation of the PHP.eB capsid 1) exceeds that reported in any previous PET study of brain uptake of targeted therapies and 2) is correlated with optical reporter gene transduction of the brain. The PHP.eB capsid brain endothelial receptor affinity is nearly 20-fold greater than that of AAV9. The results suggest that novel PET imaging techniques can be applied to inform and optimize capsid design.

/pdf/positron-emission-tomography-imaging-of-novel-aav-capsids-5q0h9eeveo.pdf

Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation.

199 Objectives: Although multiple disease-modifying immunomodulatory therapies are available for relapsing-remitting multiple sclerosis (RR-MS)1, therapeutic selection and monitoring is hampered by the lack of sensitive central nervous system (CNS) immune biomarkers Increasing evidence indicates that the presence, extent, and spatiotemporal dynamics of activated myeloid cells (ie, macrophages, microglia, monocytes, neutrophils, and dendritic cells) have the potential to serve as clinically meaningful biomarkers of active MS2 Hence, there is a critical need for non-invasive molecular imaging strategies to accurately quantify and track myeloid cells and their functional phenotypes in MS patients We previously identified triggering receptor expressed on myeloid cells 1 (TREM1) as a highly-specific marker of pro-inflammatory peripheral myeloid cells, developed the first TREM1-targeted positron emission tomography (PET) probe and demonstrated the ability of TREM1-PET to track CNS-infiltrating peripheral myeloid cells in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS3,4 Here, we investigate the ability of TREM1-PET to monitor active disease in the clinically relevant relapsing-remitting (RR-EAE) mouse model of MS Additionally, we explore the potential of TREM1 as a clinical biomarker of active MS lesions via immunostaining of rare brain biopsy tissue
METHODS: Animals: SJL mice were induced with RR-EAE using PLP139-151 emulsified in immune adjuvant Mice during active EAE disease (exhibiting paresis and/or paralysis) and remission (exhibiting complete recovery following initial EAE symptoms, similar to what occurs in RR-MS patients) were used for this study Imaging: Anti-TREM1 monoclonal antibody (mAb) was DOTA-conjugated and radiolabeled with 64Cu PET/CT imaging was performed 20 h post-injection of [64Cu]TREM1-mAb (95-120 μCi, >99% RCP) Following PET, mice were perfused with saline to remove any unbound intravascular tracer and spinal cords were analyzed via high-resolution autoradiography Biopsy: Brain lesion from a drug and steroid naive tumefactive MS patient was characterized using standard immunostaining including Luxol Fast Blue and Myelin Basic Protein (demyelination), neurofilament and Bielschowsky’s Silver stain (axonal degeneration), H&E (general immune cells), CD3 (T cells) and CD20 (B cells) TREM1 staining was then performed on MS and control (non-MS) tissue
RESULTS: TREM1-PET images reveled significantly elevated signal in the spinal cords of RR-EAE mice during active disease compared to naive and EAE mice in remission (Fig 1Ai) Ex vivo autoradiography images confirmed these findings (Fig 1Aii) Quantification of PET images revealed markedly increased tracer binding in lumbar and thoracic spinal cords of diseased EAE versus naive mice (p<00001, Fig1Bi-ii) Notably, the increased signal in diseased EAE was significantly reduced in EAE mice experiencing remission (p<00001) Increased TREM1-PET signal was also observed in the brains of EAE versus naive mice (p<005-p<00001, Fig 1Biii-vi), with a significant decrease in signal in the whole brains and medulla of EAE remission mice (p<005) Immunostaining of MS brain biopsy tissue confirmed the presence of MS pathophysiology with significant demyelination, axonal degeneration and immune cell infiltration (Fig2) Moreover, TREM1+ cells were identified in perivascular regions and TREM1 staining was substantially increased in MS compared to non-MS control tissue
CONCLUSION: TREM1-PET successfully discriminated active disease and remission in RR-EAE mice Furthermore, this is the first report of the presence of TREM1+ cells in human MS brain Thus, TREM1-PET has high potential for clinical impact on disease and therapeutic monitoring for individual RR-MS patients

TREM1-PET imaging of pro-inflammatory myeloid cells distinguishes active disease from remission in Multiple Sclerosis

16 Objectives: Parkinson’s disease (PD) is the most prevalent movement disorder and one of the most common neurodegenerative conditions, second only to Alzheimer’s disease. The pathogenesis of PD is characterized by the loss of dopaminergic neurons in the substantia nigra and the accumulation of misfolded ⍺-synuclein protein within the cytoplasm. Importantly, PD is also strongly associated with aberrant adaptive and innate immune system responses, including microglial activation and infiltration of peripheral myeloid cells into the central nervous system (CNS). TREM1 is a promising new biomarker of proinflammatory innate immune cells including macrophages, microglia, monocytes, and neutrophils. Herein, we evaluate the utility of TREM1-PET for detecting innate immune activation in the CNS of mice after intra-striatal injection of the selective dopaminergic neurotoxin, 6-hydroxydopamine (6-OHDA) - a widely-used animal model of PD.
 Methods: Twenty C57/BL6J mice were stereotaxically injected with either 6-OHDA (10 µg/µL in 1µL; n = 14) or saline (1 µL; n = 6) in their left striatum (coordinates: A/P = 0.5, L = 1.8, D/V = -3.5; Fig. 1). Additionally, three TREM1-knockout mice were injected with 6-OHDA (n = 3). On either day 7 or 14 post-surgery, mice were administered with [64Cu]TREM1-mAb (n = 18) or [64Cu]Isotype control-mAb (n = 5) and imaged by whole-body PET/CT after 19 hours. Ex vivoautoradiography (ARG) was performed to obtain high resolution images of tracer uptake within the striatum, and ratios of tracer signal in the ipsilateral versus contralateral striatum were quantified for both PET and ARG. Statistically, all groups were compared to the saline control cohort.
 Results: Copper-64 radiolabeling of TREM1 mAb (chelator:mAb ratio = 0.96) and isotype control (chelator:mAb ratio = 1.9) resulted in 25% and 80% decay-corrected radiochemical yield, respectively (radiochemical purity > 99%). PET/CT images revealed TREM1-positive activated myeloid cells in the damaged brain hemisphere of 6-OHDA injected mice. PET image analysis verified significant tracer signal within the ipsilateral striatum of 6-OHDA compared to the saline-injected mice at 7 days post-surgery (P < 0.0146; Fig. 1a), which was corroborated by ex vivo ARG (P < 0.0202; Fig. 1b). Specificity of this signal was shown by the lack of significant binding in the ipsilateral striatum of TREM1-KO mice in addition to 6-OHDA mice imaged with [64Cu]Isotype control-mAb - all 7 days post-surgery. Conversely, there was no difference between saline mice and those injected with 6-OHDA at 14 days post-surgery, indicating that TREM1-PET may only be useful as an early biomarker of neuroinflammation in this model.
 Conclusions: TREM1-PET represents a promising, highly specific, approach for visualizing the presence of early innate immune activation in PD rodent models. Notably, elevated levels of activated myeloid cells could be detected within the CNS of 6-OHDA injected mice in vivo using [64Cu]TREM1-mAb. Further investigation of this tracer is warranted in other PD rodent models and human postmortem tissue to assess its translational potential.
Supporting Data:Figure 1. A) PET image analysis of mice injected with 6-OHDA or saline (N = 23; Saline n = 4, Day 7 n = 3, Day 14 n = 8, Isotype Ctrl n = 5, TREM1-KO n = 3), showing the ratio of tracer signal in the ipsilateral striatum over that in the contralateral striatum. B) Ex vivo autoradiography (ARG) of mice induced with 6-OHDA or saline, showing significant (P

Visualizing innate immune activation in a mouse model of Parkinson’s disease using a highly specific TREM1-PET tracer.

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Neuroinflammation PET Imaging: Current Opinion and Future Directions.

Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation.

TREM1-PET imaging of pro-inflammatory myeloid cells distinguishes active disease from remission in Multiple Sclerosis

Visualizing innate immune activation in a mouse model of Parkinson’s disease using a highly specific TREM1-PET tracer.