The exceptional nature of the rht‐MOF platform, based on a singular edge‐transitive net (the only net for the combination of 3‐ and 24‐connected nodes), makes it an ideal target in crystal chemistry. The high level of control indicates an unparalleled blueprint for isoreticular functional materials (without concern for interpenetration) for targeted applications.
There is a critical need to develop and rigorously validate molecular imaging biomarkers to aid diagnosis and characterization of primary brain tumors. Elevated expression of translocator protein (TSPO) has been shown to predict disease progression and aggressive, invasive behavior in a variety of solid tumors. Thus, noninvasive molecular imaging of TSPO expression could form the basis of a novel, predictive cancer imaging biomarker. In quantitative preclinical PET studies, we evaluated a high-affinity pyrazolopyrimidinyl-based TSPO imaging ligand, N,N-diethyl-2-(2-(4-(2-(18F)-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ([18F]DPA-714), as a translational probe for quantification of TSPO levels in glioma.
Methods
Glioma-bearing rats were imaged with [18F]DPA-714 in a microPET system. Dynamic images were acquired simultaneously upon injection of [18F]DPA-714 (130 – 200 MBq/0.2 mL). Arterial blood was collected to derive the input function (AIF), with HPLC radiometabolite analysis performed upon select samples for AIF correction. Compartmental modeling was performed using the corrected AIF. Specific tumor cell binding of DPA-714 was evaluated by radioligand displacement of [3H]PK 11195 with DPA-714 in vitro and displacement of [18F]DPA-714 with excess DPA-714 in vivo. Immediately following imaging, tumor and healthy brain tissues were harvested for validation by western blotting and immunohistochemistry.
Results
[18F]DPA-714 was found to preferentially accumulate in tumors with modest uptake in contralateral brain. Infusion with DPA-714 (10 mg/kg) displaced [18F]DPA-714 binding by greater than 60% on average. Tumor uptake of [18F]DPA-714 was similar to another high-affinity TSPO imaging ligand, [18F]PBR06, and agreed with ex vivo assay of TSPO protein levels in tumor and healthy brain.
Conclusions
These studies illustrate the feasibility of using [18F]DPA-714 for visualization of TSPO-expressing brain tumors. Importantly, [18F]DPA-714 appears suitable for quantitative assay of tumor TSPO levels in vivo. Given the relationship between elevated TSPO levels and poor outcome in oncology, these studies suggest the potential of [18F]DPA-714 PET to serve as a novel predictive cancer imaging modality.
A new pillaring strategy, based on a ligand-to-axial approach that combines the two previous common techniques, axial-to-axial and ligand-to-ligand, and permits design, access, and construction of higher dimensional MOFs, is introduced and validated. Trigonal heterofunctional ligands, in this case isophthalic acid cores functionalized at the 5-position with N-donor (e.g., pyridyl- or triazolyl-type) moieties, are designed and utilized to pillar pretargeted two-dimensional layers (supermolecular building layers, SBLs). These SBLs, based on edge transitive Kagomé and square lattices, are cross-linked into predicted three-dimensional MOFs with tunable large cavities, resulting in isoreticular platforms.
Focused library synthesis and structure-activity relationship development of 5,6,7-substituted pyrazolopyrimidines led to the discovery of 2-(5,7-diethyl-2-(4-(2-fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (6b), a novel translocator protein (TSPO) ligand exhibiting a 36-fold enhancement in affinity compared to another pyrazolopyrimidine-based TSPO ligand, 6a (DPA-714). Radiolabeling with fluorine-18 (18F) facilitated production of 2-(5,7-diethyl-2-(4-(2-[18F]fluoroethoxy)phenyl)pyrazolo[1,5-a]pyrimidin-3-yl)-N,N-diethylacetamide (18F-6b) in high radiochemical yield and specific activity. In vivo studies of 18F-6b were performed which illuminated this agent as an improved probe for molecular imaging of TSPO-expressing cancers.
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