Search

α-synuclein (α-syn) pathologies are central to the development of synucleinopathies including Parkinson's disease (PD). Positron emission tomography (PET) imaging of α-syn pathologies is one strategy to facilitate the diagnosis, understanding, and treatment of synucleinopathies, but has been restricted by the lack of specific α-syn PET probes. In this work, we identified 2,6-disubstituted imidazo[2,1- b ][1,3,4]thiadiazole (ITA) as a new α-syn-binding scaffold. Through autoradiography studies, we discovered an iodinated lead compound [ 125 I] ITA-3 , with moderate binding affinity (IC 50 = 55 nM) to α-syn pathologies in human PD brain sections. Modified from [ 125 I] ITA-3 , we developed a potential PET tracer, [ 18 F] FITA-2 (radiochemical yield >25%, molar activity >110 GBq/μmol), which demonstrated clear signals in α-syn-rich regions in human PD brain tissues (IC 50 = 245 nM), good brain uptake (SUV peak = 2.80 ± 0.45), and fast clearance rate in rats. Overall, [ 18 F] FITA-2 appears to be a promising candidate for α-syn PET imaging and merits further development.

Novel ligands with the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or 5,6-dimethoxyisoindoline pharmacophore were designed and synthesized for evaluation of their structure-activity relationship to the sigma-2 (σ 2 ) receptor and developed as suitable PET radioligands. Compound 1 was found to possess nanomolar affinity ( K i (σ 1 ) = 2.57 nM) for the σ 2 receptor, high subtype selectivity (>2000-fold), and high selectivity over 40 other receptors and transporters. Radioligand [ 18 F] 1 was prepared with radiochemical yield of 37-54%, > 99% radiochemical purity, and molar activity of 107-189 GBq/μmol. Biodistribution and blocking studies in mice and micro-PET/CT imaging of [ 18 F] 1 in rats indicated excellent binding specificity to the σ 2 receptors in vivo . Micro-PET/CT imaging of [ 18 F] 1 in the U87MG glioma xenograft model demonstrated clear tumor visualization with high tumor uptake and tumor-to-background ratio. Co-injection with CM398 (5 μmol/kg) led to a remarkable reduction of tumor uptake (80%, 60-70 min), indicating high specific binding of [ 18 F] 1 in U87MG glioma xenografts.

Radioisotope-labeled prostate-specific membrane antigen (PSMA) PET tracers have gained popularity in diagnosing prostate cancer (PCa). This study aimed to improve the affinity and tumor-targeting capabilities of new PSMA tracers by increasing the number of pharmacophores that specifically bind to PSMA. Using biphenyl as a core scaffold, we investigated the relationship among spacer segments, affinity, and pharmacokinetic properties. In preclinical PET studies on mice with 22Rv1 tumors, compared with [ 68 Ga]Ga- PSMA-11 (SUV max = 3.37), [ 68 Ga]Ga- PSMA-D5 ( K i = 0.15) showed higher tumor uptake (SUV max = 3.51) and lower renal uptake (T/K = 1.84). In the first-in-human study, [ 68 Ga]Ga- PSMA-D5 effectively detected small PCa-associated lesions and distant metastases. The advantages of [ 68 Ga]Ga- PSMA-D5 include high tumor uptake, straightforward synthesis, and labeling, making it a promising PSMA PET tracer. Furthermore, [ 68 Ga]Ga- PSMA-D5 contains a DOTA chelator, allowing convenient labeling with therapeutic radionuclides such as 177 Lu and 225 Ac, providing the potential for targeted radioligand therapy in PCa.

Tau accumulation is one of the predominant neuropathological biomarkers for in vivo diagnosis of Alzheimer's disease due to its high correlation with disease progression. In this study, we focused on the structure-activity relationship study of the substituent effect on the aza-fused tricyclic core imidazo[1,2-h][1,7]naphthyridine to screen 18 F-labeled Tau tracers. Through a series of autoradiographic studies and biological evaluations, 4-[ 18 F]fluorophenyl-substituted tracer [ 18 F] 13 ([ 18 F] FPND-4 ) was identified as a promising candidate with high affinity to native Tau tangles (IC 50 = 2.80 nM), few appreciable binding to Aβ plaques and MAO-A/B. Validated by dynamic positron emission tomography (PET) imaging in rodents and rhesus monkey, [ 18 F] 13 displayed desirable brain uptake (SUV = 1.75 at 2 min), fast clearance (brain 2min/60min = 5.9), minimal defluorination, and few off-target binding, which met the requirements of a Tau-specific PET radiotracer.

A series of fluoro-pegylated (FPEG) 2-pyridinylbenzoxazole and 2-pyridinylbenzothiazole derivatives were synthesized and evaluated as novel β-amyloid (Aβ) imaging probes for PET. They displayed binding affinities for Aβ(1-42) aggregates that varied from 2.7 to 101.6 nM. Seven ligands with high affinity were selected for (18)F labeling. In vitro autoradiography results confirmed the high affinity of these radiotracers. In vivo biodistribution experiments in normal mice indicated that the radiotracers with a short FPEG chain (n = 1) displayed high initial uptake into and rapid washout from the brain. One of the 2-pyridinylbenzoxazole derivatives, [(18)F]-5-(5-(2-fluoroethoxy)benzo[d]oxazol-2-yl)-N-methylpyridin-2-amine ([(18)F]32) (K(i) = 8.0 ± 3.2 nM) displayed a brain(2min)/brain(60min) ratio of 4.66, which is highly desirable for Aβ imaging agents. Target specific binding of [(18)F]32 to Aβ plaques was validated by ex vivo autoradiographic experiment with transgenic model mouse. Overall, [(18)F]32 is a promising Aβ imaging agent for PET and merits further evaluation in human subjects.