Purpose
In vivo detection of transactivation response element DNA binding protein-43 kDa (TDP-43) aggregates through positron emission tomography (PET) would impact the ability to successfully ...develop therapeutic interventions for a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). The purpose of the present study is to evaluate the ability of six tau PET radioligands to bind to TDP-43 aggregates in post-mortem brain tissues from ALS patients.
Procedures
Herein, we report the first head-to-head evaluation of six tritium labeled isotopologs of tau-targeting PET radioligands,
3
HMK-6240 (a.k.a. florquinitau),
3
HGenentech Tau Probe-1 (GTP-1),
3
HJNJ-64326067(JNJ-067),
3
HCBD-2115,
3
Hflortaucipir, and
3
HAPN-1607, and their ability to bind to the β-pleated sheet structures of aggregate TDP-43 in post-mortem ALS brain tissues by autoradiography and immunostaining methods. Post-mortem frontal cortex, motor cortex, and cerebellum tissues were evaluated, and binding intensity was aligned with areas of elevated phosphorylated tau (ptau), pTDP-43, and
β
-amyloid.
Results
Negligible binding was observed with
3
HMK-6240,
3
HJNJ-067, and
3
HGTP-1. While
3
HCBD-2115 displayed marginal specific binding, this binding did not significantly correlate with the distribution of pTDP-43 and AT8 inclusions. Of the remaining ligands, the distribution of
3
Hflortaucipir did not significantly correlate to pTDP-43 pathology; however, specific binding trends to a positive relationship with tau. Finally,
3
HAPN-1607 relates most strongly to amyloid load and does not indicate pTDP-43 pathology as confirmed by
3
HPiB distribution in sister sections.
Conclusions
Our results demonstrate the prominent nature of mixed pathology in ALS, and do not support the application of
3
HMK-6240,
3
HJNJ-067,
3
HGTP-1,
3
HCBD-2115,
3
Hflortaucipir, or
3
HAPN-1607 for selective imaging TDP-43 in ALS for clinical research with the currently available in vitro data. Identification of potent and selective radiotracers for TDP-43 remains an ongoing challenge.
Success of gene therapy relies on the durable expression and activity of transgene in target tissues. In vivo molecular imaging approaches using positron emission tomography (PET) can non-invasively ...measure magnitude, location, and durability of transgene expression via direct transgene or indirect reporter gene imaging in target tissues, providing the most proximal PK/PD biomarker for gene therapy trials. Herein, we report the radiosynthesis of a novel PET tracer 18FAGAL, targeting alpha galactosidase A (α-GAL), a lysosomal enzyme deficient in Fabry disease, and evaluation of its selectivity, specificity, and pharmacokinetic properties in vitro. 18FAGAL was synthesized via a Cu-catalyzed click reaction between fluorinated pentyne and an aziridine-based galactopyranose precursor with a high yield of 110 mCi, high radiochemical purity of >97% and molar activity of 6 Ci/µmol. The fluorinated AGAL probe showed high α-GAL affinity with IC50 of 30 nM, high pharmacological selectivity (≥50% inhibition on >160 proteins), and suitable pharmacokinetic properties (moderate to low clearance and stability in plasma across species). In vivo 18FAGAL PET imaging in mice showed high uptake in peripheral organs with rapid renal clearance. These promising results encourage further development of this PET tracer for in vivo imaging of α-GAL expression in target tissues affected by Fabry disease.
Dany Laferrière has demonstrated a continuous engagement with Japan, beginning with the novel Éroshima in 1987 and continuing to his most recent publication in 2021, Sur la route avec Bashō. The aim ...of this article is to understand what role Japan plays within Laferrière's writing and how it helps us understand the complex network of sex, power, and race in his work. Between the cosmopolitanism of the network of nation-states and the despair of identity politics, I situate Laferrière's use of Japan as a fantasy that empowers the writer beyond the impasse of a white-black racial imaginary. Reading Laferrière this way allows us to understand how his writing uses the fantasy of the Orient, often to the detriment of Asian women. As such it contributes to comparative work between Asian and French literatures, debates in Francophonie, and critical understandings of race in the Francophone sphere of the Americas.
Purpose
The purpose of this study was to evaluate the binding specificity of the radiolabeled glucagon-like peptide 1 receptor (GLP-1R) agonist (Lys
40
(DOTA)NH
2
)Exendin-4 in the pancreas using a ...combination of
ex vivo
autoradiography and immunohistochemistry.
Procedures
Sprague–Dawley rats were administered
64
Cu(Lys
40
(DOTA)NH
2
)Exendin-4 i.v. with or without unlabeled Exendin (9-39) to determine binding specificity. Similar experiments were performed using Zucker diabetic fatty (ZDF) and Zucker lean (ZLC) rats. Animals were euthanized and the pancreas was extracted, immediately frozen, and sectioned. The sections were apposed to phosphor imaging plates, scanned, and immunostained for insulin.
Results
Co-registration of the autoradiographic and immunohistochemical images revealed that
64
Cu (Lys
40
(DOTA)NH
2
)Exendin-4 specific binding was restricted to islet cells. This binding was blocked by the co-administration of Exendin(9-39) indicating that the radiotracer uptake is mediated by GLP-1R. Uptake of
64
Cu(Lys
40
(DOTA)NH
2
)Exendin-4 was greatly decreased in the pancreas of ZDF rats.
Conclusions
Ex vivo
autoradiography results using
64
Cu(Lys
40
(DOTA)NH
2
)Exendin-4 suggest that GLP-1R agonists based on Exendin-4 are attractive PET ligands for the
in vivo
determination of β-cell mass.
This review will discuss the production and applications of positron-emitting radionuclides for use in Positron Emission Tomography (PET), with emphasis on radionuclides that can be produced onsite ...with a biomedical cyclotron. In PET the traditional radionuclides of choice are 11C, 13N, 15O and 18F and although they will be briefly discussed in this article, the emphasis of this review will be on non-standard PET radionuclides that are generating increased interest by the medical research community.
Success of gene therapy relies on the durable expression and activity of transgene in target tissues. In vivo molecular imaging approaches using positron emission tomography (PET) can non-invasively ...measure magnitude, location, and durability of transgene expression via direct transgene or indirect reporter gene imaging in target tissues, providing the most proximal PK/PD biomarker for gene therapy trials. Herein, we report the radiosynthesis of a novel PET tracer sup.18FAGAL, targeting alpha galactosidase A (α-GAL), a lysosomal enzyme deficient in Fabry disease, and evaluation of its selectivity, specificity, and pharmacokinetic properties in vitro. sup.18FAGAL was synthesized via a Cu-catalyzed click reaction between fluorinated pentyne and an aziridine-based galactopyranose precursor with a high yield of 110 mCi, high radiochemical purity of >97% and molar activity of 6 Ci/µmol. The fluorinated AGAL probe showed high α-GAL affinity with ICsub.50 of 30 nM, high pharmacological selectivity (≥50% inhibition on >160 proteins), and suitable pharmacokinetic properties (moderate to low clearance and stability in plasma across species). In vivo sup.18FAGAL PET imaging in mice showed high uptake in peripheral organs with rapid renal clearance. These promising results encourage further development of this PET tracer for in vivo imaging of α-GAL expression in target tissues affected by Fabry disease.
Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here ...we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood-brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD.
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