[(18)F]T807 demonstrates high affinity and selectivity to PHF-tau as well as favorable in vivo properties, making this a promising candidate as an imaging agent for AD.
We are developing assays for noninvasive, quantitative imaging of reporter genes with positron emission tomography (PET), for application both in animal models and in human gene therapy. We report here a method to improve the detection of lower levels of PET reporter gene expression by utilizing a mutant herpes simplex virus type 1 thymidine kinase (HSV1-sr39tk) as a PET reporter gene.
Several approaches are being developed to image reporter gene expression in living animals. These include methods that rely on charge-coupled device camera imaging and bioluminescent reporter genes (1), single-photon emission computed tomography using the herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene (2), approaches that use magnetic resonance imaging (reviewed in ref.3), methods based on the HSV1-tk reporter gene and positron emission tomography (PET) (4, 5), and the use of the dopamine type 2 receptor (D2R) as a reporter gene for PET (6). The use of reporter genes that can be imaged in vivo will permit many different applications, including monitoring of both somatic gene transfer and transgenic͞knock-in reporter gene expression (7).PET provides repeated, noninvasive imaging of biological processes in living subjects (8, 9). PET utilizes molecular probes labeled with positron-emitting radioisotopes (e.g., fluorine-18, with a half-life of 110 min). PET probes typically are either positron-labeled ligands for receptors or positron-labeled substrates for intracellular enzymes. Tracer quantities of PET probes yield a tomographic image after their retention, as a consequence of either binding of positron-labeled ligand to a receptor or conversion of positron-labeled substrate to ''trapped'' metabolic product(s). PET is particularly well suited for application to human studies. PET reporter gene imaging in humans will allow monitoring of the location(s), magnitude, and duration of therapeutic͞suicide gene expression, by using vectors for DNA delivery in which the reporter gene and therapeutic gene are expressed from a common transcript (10,11 HSV1-tk refers to the gene, HSV1-TK refers to the enzyme.) HSV1-TK phosphorylates a range of substrates, including acycloguanosines (e.g., acyclovir, ganciclovir, penciclovir) and uracil derivatives [e.g., 2Ј-f luoro-2Ј-deoxy-1--arabinofuranosyl-5-iodouracil (FIAU)]. In contrast, mammalian thymidine kinases phosphorylate acycloguanosines only minimally, making these substrates advantageous as reporter gene imaging probes (11). Acycloguanosine derivatives are currently used extensively both as cytotoxic pharmaceuticals to treat herpes infections and for HSV1-tk suicide gene therapy (13).Improvements in sensitivity of the HSV1-tk reporter gene imaging assay can be achieved either (i) by identifying substrates that exhibit higher V max ͞K m for HSV1-TK or (ii) by engineering TK enzyme(s) with improved V max ͞K m for a particular reporter substrate. Decreased V max ͞K m of HSV1-TK for thymidine (an endogenous competitor) also should improve HSV1-tk reporter gene assay sensiti...
Senile plaques and neurofibrillary tangles are prominent neuropathological hallmarks in Alzheimer's disease and are considered to be targets for therapeutic intervention as well as biomarkers for diagnostic in vivo imaging agents. While there are a number of amyloid-β positron emission tomography (PET) tracers currently in different stages of clinical development and commercialization, there have been very few reports on imaging agents selectively targeting tau aggregates. In search of [18F]-PET tracers that possess great binding affinity and selectivity toward tau tangles, we tested more than 900 compounds utilizing a unique screening process. A competitive autoradiography assay was set up to test compounds for binding to native tau tangles and amyloid-β plaques on human brain tissue sections. In our in vitro assays, the 18F labeled compound [18F]-T808 displayed a high level of binding affinity and good selectivity for tau aggregates over amyloid-β plaques. [18F]-T808 showed rapid uptake and washout in rodent brains. Our in vitro and preclinical in vivo studies suggest that [18F]-T808 possesses suitable properties and characteristics to be a specific and selective PET probe for imaging of paired helical filament tau in human brains.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.