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Lewy pathologies, which mainly consist of insoluble α-synuclein (α-syn) aggregates, are the hallmarks of Parkinson's disease and many other neurodegenerative diseases termed "synucleinopathies". Detection of Lewy pathologies with optical methods is of interest for preclinical studies, while the α-syn fluorescent probe is still in great demand. By rational design, we obtained a series of D-π-A-based trisubstituted alkenes with acceptable optical properties and high binding affinities to α-syn fibrils. Among these probes, FPQXN and TQXN-2 exhibited high binding affinities (6 and 8 nM, respectively), significant fluorescence enhancements (17.2- and 26.6-fold, respectively), and satisfying quantum yields (36.5% and 10.4%, respectively), which met the need for the in vitro neuropathological staining of Lewy pathologies in the PD brain sections. In addition, TQXN-2 showed great potential in fluorescent discrimination of Lewy pathologies and Aβ plaques. Our research provides flexible tools for in vitro detection of α-syn aggregates and offers new structural frameworks for the further development of α-syn fluorescent probes.

This review provides an essential overview on the progress of rapidly-developing China’s radiopharmaceuticals in recent years (2014–2021). Our discussion reflects on efforts to develop potential, preclinical, and in-clinical radiopharmaceuticals including the following areas: (1) brain imaging agents, (2) cardiovascular imaging agents, (3) infection and inflammation imaging agents, (4) tumor radiopharmaceuticals, and (5) boron delivery agents (a class of radiopharmaceutical prodrug) for neutron capture therapy. Especially, the progress in basic research, including new radiolabeling methodology, is highlighted from a standpoint of radiopharmaceutical chemistry. Meanwhile, we briefly reflect on the recent major events related to radiopharmaceuticals along with the distribution of major R&D forces (universities, institutions, facilities, and companies), clinical study status, and national regulatory supports. We conclude with a brief commentary on remaining limitations and emerging opportunities for China’s radiopharmaceuticals.

Six indole-based derivatives with a methoxy group at the indole ring were synthesized and evaluated as σ2 receptor ligands with nanomolar affinity (Ki (σ2) = 4.40-9.46 nM) and moderate subtype selectivity (Ki(σ2)/Ki(σ1) = 7-102). Radioligands 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[18F]fluoroethoxy)-1H-indole ([18F]3) and 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-5-(2-[18F]fluoroethoxy)-1H-indole ([18F]4) with high σ2 receptor affinity and subtype selectivity were synthesized through a direct SN2 displacement reaction, with radiochemical yields of 36-50% and 20-29%, radiochemical purity of >99%, and molar activities of 29-151 GBq/μmol and 55-72 GBq/μmol, respectively. Radioligand [18F]3 displayed high brain uptake, high brain-to-blood ratio and slow washout from the brain in male ICR mice. Administration of compound CM398 5 min prior to the radiotracer injection led to a significantly dose-dependent reduction of the brain accumulation (29-54%) and the brain-to-blood ratio (60-88%) at 30 min, indicating high specific binding of [18F]3 to the σ2 receptors in the brain. Ex vivo autoradiography in male ICR mice showed widely and heterogeneous distribution of [18F]3 in the brain. Small animal positron emission tomography imaging in rats confirmed different distribution and high specific binding of [18F]3 to σ2 receptors in rat brain. These findings warrant [18F]3 as a potential probe used for neuroimaging of the σ2 receptors in the brain.

Neurofibrillary tangles (NFTs), which are composed of abnormally hyperphosphorylated Tau, are one of the main pathologic hallmarks of Alzheimer's disease and other tauopathies. The fluorescent imaging probes currently used to target NFTs cannot distinguish them well from β-amyloid plaques, thus limiting their utility to diagnose diseases. Here, we developed a fused cycloheptatriene-BODIPY derivative (

Tau aggregation is believed to have a strong association with the level of cognitive deficits in Alzheimer's disease (AD). Thus, optical brain imaging of tau aggregates has recently gained substantial attention as a promising tool for the early diagnosis of AD. However, selective imaging of tau aggregates is a major challenge due to sharing similar β-sheet structures with homologous Aβ fibrils. Herein, four quinoline-based fluorescent probes (Q-tau) were judiciously designed using the donor-acceptor architecture for selective imaging of tau aggregates. In particular, probe Q-tau 4 exhibited a strong intramolecular charge transfer and favorable photophysical profile, such as a large Stokes' shift and fluorescence emission wavelength of 630 nm in the presence of tau aggregates. The probe also displayed a "turn-on" fluorescence behavior toward tau fibrils with a 3.5-fold selectivity versus Aβ fibrils. In addition, Q-tau 4 exhibited nanomolar binding affinity to tau aggregates (Kd = 16.6 nM), which was 1.4 times higher than that for Aβ fibrils. The mechanism of "turn-on" fluorescence was proposed to be an environment-sensitive molecular rotor-like response. Moreover, ex vivo labeling of human AD brain sections demonstrated favorable colocalization of Q-tau 4 and the phosphorylated tau antibody, while comparable limited staining was observed with Aβ fibrils. Molecular docking was conducted to obtain insights into the tau-binding mode of the probe. Collectively, Q-tau 4 has successfully been used as a tau-specific fluorescent imaging agent with lower background interference.

The presence of Aβ plaques in the brain is a hallmark of Alzheimer's disease. Here, we designed and synthesized a series of molecular rotors with various bi-aromatic rings and investigated their applications as near-infrared (NIR) probes for Aβ plaques. We found that the interaction with Aβ aggregates hindered the rotational freedom of the molecular rotors, which brought about a noticeable enhancement in fluorescence intensity. Among them, probe 4b (K

The highly rigid and planar scaffolds with π-conjugated systems have been widely considered to be indispensable for β-amyloid (Aβ) binding ligands. In this study, a library of diphenoxy compounds with different types of more flexible linkers as Aβ ligands were synthesized and evaluated. Most of them displayed good affinity (Ki < 100 nM) for Aβ1-42 aggregates, and some ligands even showed values of Ki less than 10 nM. Structure-activity relationship analysis revealed that modification on the linkers or substituents tolerated great flexibility, which challenged the long-held belief that rigid and planar structures are exclusively favored for Aβ binding. Three ligands were labeled by iodine-125, and they exhibited good properties in vitro and in vivo, which further supported that this flexible scaffold was potential and promising for the development of Aβ imaging agents.

In this study, a series of organo difluoroboron probes with a BF2 benzamide moiety was designed, prepared and evaluated. Among them, 2c displayed the best optical and biological properties, and may be used as a useful near-infrared fluorescent probe for the detection of Aβ plaques and neurofibrillary tangles in AD.

α-Synuclein aggregates abnormally into intracellular inclusions in Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and many other neurological disorders, closely connecting with their pathogenesis. The accurate tracking of α-synuclein by targeting probes is of great significance for early diagnosis, disease monitoring, and drug development. However, there have been no promising α-synuclein targeting probes for clinical application reported so far. This overview focuses on various potential α-synuclein targeting probes reported in the past two decades, including small-molecule fluorescent probes and radiolabeled probes. We provide the current status of the development of the small molecular α-synuclein imaging probes, including properties of promising imaging molecules, strategies of processing new probes, limited progress, and growth prospects in this field, expecting to help in the further development of α-synuclein targeting probes.

For various neurodegenerative diseases, including Alzheimer's disease (AD), the abnormal aggregation of Tau is not only the predominant contributing factor but also a major biomarker for disease diagnosis. In this study, a series of aza-fused tricyclic derivatives were designed and synthesized. By changing the position and number of nitrogen atoms on the fused tricyclic core, the imidazonaphthyridine scaffold was screened and reported for the first time which could potentially detect Tau aggregates. Through a series of in vitro and in vivo biological evaluations, probe [

PurposeThis prospective trial aimed to evaluate the safety, dosimetry, biodistribution, and diagnostic efficacy of a novel theranostic probe 68Ga-DOTA-DiPSMA. Also, we have performed the first comparison with 68Ga-PSMA-11 in prostate cancer (PCa) patients.MethodsFive healthy volunteers and ten PCa patients with a previous clinical 68Ga-PSMA-11 PET/CT were injected with an intravenous bolus of 68Ga-DOTA-DiPSMA with a dose of 1.85MBq/kg. Healthy volunteers received serial whole-body PET scans from the time of injection up to 60 min post-injection, with a second PET/CT scanning at 120 min post-injection. In PCa patients, low-dose CT scan, whole-body PET was performed with 2 min per bed position in 40 min post-injection. In addition, 68Ga-PSMA-11 scanning was performed on PCa patients within 10 days under the same acquisition procedure. Absorbed organ doses and effective doses were calculated using OLINDA/EXM. Normal organ uptake and tumor lesion uptake (SUVmax) were measured. A lesion-by-lesion analysis was performed.Results 68Ga-DOTA-DiPSMA administration was safe and well-tolerated. The kidneys received the highest absorbed dose (114.46 ± 29.28 uSv/MBq), followed by the urinary bladder wall (100.82 ± 46.22 uSv/MBq) in accordance with the expected PSMA renal excretion of the tracer. The mean effective dose was 19.46 ± 1.73 μSv/MBq. The SUVmax of 68Ga-PSMA-11 and 68Ga-DOTA-DiPSMA PET/CT for PCa lesions, bone metastases, and lymph node metastases were 11.2 ± 10.76 vs. 4.41 ± 2.72, 7.6 ± 1.58 vs. 2.95 ± 1.11 and 4.86 ± 1.94 vs. 3.26 ± 1.2, respectively.ConclusionInjection of 68Ga-DOTA-DiPSMA is safe and associated with low absorbed and effective doses. Compared to 68Ga-PSMA-11, 68Ga-DOTA-DiPSMA shows comparable pharmacokinetics and detection ability in PCa patients that warrant further head-to-head comparison. Low non-specific uptake in salivary glands and kidneys of 68Ga-DOTA-DiPSMA indicates potential radioligand therapy (RLT) application when labeled with 177Lu, 90Y, or 225Ac.

β-Amyloid (Aβ) plaques and Tau tangles are cognitive impairment markers vital for diagnosing and preventing Alzheimer's disease (AD). To systematically explore the relationship between the number or position of nitrogen atoms and their optical properties and biological properties, five series of new N, O-coordinated organo-difluoroboron probes were introduced as binding scaffolds for Aβ plaques and Tau tangles. These probes exhibited suitable optical properties for near-infrared (NIR) imaging. Probe 4PmNO-2 (4-((1E,3E)-4-(1,1-difluoro-1H-1λ4,9λ4-pyrimido[1,6-c][1,3,5,2]oxadiazaborinin-3-yl)buta-1,3-dien-1-yl)-N,N-dimethylaniline) displayed the excellent emission maximum (716 nm in PBS), a high quantum yield (61.4% in CH2Cl2), and a high affinity for synthetic Aβ1–42 (Kd = 23.64 ± 1.08 nM) and Tau (K18) aggregates (Kd = 26.38 ± 1.29 nM), as well as for native Aβ plaques and NFTs in the brain tissue from AD patients. 4PmNO-2, with significantly enhanced fluorescence (Aβ1–42, 136 fold; Tau (K18), 96 fold) and the highest initial brain uptake (11.57% ID/g at 2 min) in normal ICR mice, was evaluated further. In vivo NIR fluorescent imaging studies in living Aβ and Tau transgenic mice revealed that it could differentiate healthy and diseased animals. Further ex vivo fluorescent staining studies showed that 4PmNO-2 specifically bound to Aβ plaques and Tau tangles in transgenic mice. In summary, the probe 4PmNO-2 may be a useful near-infrared fluorescence (NIRF) probe for AD biomarkers.

The early noninvasive diagnosis of Alzheimer's disease targeted β-amyloid (Aβ) plaques or Tau tangles is a major challenge because of the coshared β-sheet structure of the target. In contrast to tailoring probes to specific amyloids, here, we showed that near-infrared (NIR) environment-sensitive probe 18 could fluorescently discriminate Aβ and Tau from artificial aggregates to pathological change in the brain tissue. The biological evaluation demonstrated that the substantial fluorescence enhancement, large blueshift in the emission upon interactions with the aggregates, and the high binding affinity significantly contributed to the fluorescent discrimination. A simplified Ooshika-Lippert-Mataga equation provided an effective means of correlating 18 with the static relative permittivity (e0) of proteins, elucidating the origin of the distinction capabilities, and quantitatively estimating the dielectric properties of proteins. Moreover, 18 possessed high bioavailability, including sufficient blood-brain barrier penetration, in vivo NIR imaging, and ex vivo histology in living mice.

We have discovered and synthesized a series of indole-based derivatives as novel sigma-2 (

The prostate-specific membrane antigen (PSMA) is considered to be an excellent theranostic target of prostate cancer (PCa). In this study, three 18F-labeled PSMA tracers with a more lipophilic quinoline functional spacer were designed, synthesized, and evaluated based on the Glu-Ureido-Lys binding motif. The effect of structure-related lipophilic difference on distribution and excretion of these tracers in vitro and in vivo (cells, rodent, primate, and human) was investigated by comparing with [18F]DCFPyL. There is no significant correlation between the renal elimination and the lipophilicity of the tracers in all species. However, the higher the lipophilicity of tracer, the higher the radioactivity accumulation in the liver of primate and human, and the less radioactivity is to excrete to the bladder with urine. The screened tracer [18F]8c, with a Ki value of 4.58 nM, displayed notable low bladder retention and demonstrated good imaging properties in patients with PCa.

In this study, three pairs of optically pure 18F-labeled 2-phenylquinoxaline derivatives were evaluated as Tau imaging agents for the diagnosis of Alzheimer's disease (AD). The chiral 2-fluoromethyl-1,2-ethylenediol side chain was attached to the 2-phenylquinoxaline backbone to increase hydrophilicity, thereby improving the binding affinity of the probe to tangles and their selectivity toward Tau tangles over β-amyloid plaques (Aβ). These probes displayed excellent fluorescent properties and high selectivity for tangles on brain sections from transgenic mice (rTg4510) and AD patients. Quantitative binding assays with AD homogenates showed that the probes (R)-5 and (S)-16 have a high affinity (Ki = 4.1 and 10.3 nM, respectively) and high selectivity (30.5-fold and 34.6-fold, respectively) for tangles over Aβ. The high affinity and selectivity of (R)-[18F]5 and (S)-[18F]16 for tangles were further confirmed with autoradiography on AD brain tissue in vitro. In addition, they displayed sufficient blood-brain barrier penetration (7.06% and 10.95% ID/g, respectively) and suitable brain kinetics (brain2 min/brain60 min = 10.1, 6.5 respectively) in normal mice. Ex vivo metabolism studies and micro-positron emission computed tomography (PET) revealed high brain biostability, good brain kinetic properties, and low nonspecific binding for (S)-[18F]16. Together, these results demonstrate that (R)-[18F]5 and (S)-[18F]16 are promising PET probes for Tau tangles imaging.

The plaques of accumulated β-amyloid (Aβ) in the parenchymal brain are accepted as an important biomarker for the early diagnosis of Alzheimer's disease (AD). Many near-infrared (NIR) probes, which were based on the D-π-A structure and bridged by conjugated double bonds, had been reported and displayed a high affinity to Aβ plaques. Considering the isomerization caused by the polyethylene chain, however, the conjugated polyacetylene chain is a better choice for developing new NIR Aβ probes. Hence, in this report, a new series of NIR probes with naphthyl or phenyl rings and different numbers of conjugated triple bonds were designed, synthesized, and evaluated as NIR probes for Aβ plaques. Upon interaction with Aβ aggregates, these probes displayed a significant increase in fluorescence intensity (45- to 360-fold) and a high to moderate affinity (6.05-56.62 nM). Among them, probe 22b displayed excellent fluorescent properties with a 183-fold increase in fluorescence intensity and an emission maximum at 650 nm after incubated with Aβ aggregates. Furthermore, 22b had a high affinity to Aβ aggregates (Kd = 12.96 nM) and could efficiently detect the Aβ plaques in brain sections from both transgenic mice and AD patients in vitro. In summary, this work may lead to a new direction in the development of novel NIR probes for the detection of Aβ plaques.

A novel and efficient method for the synthesis of difluoroalkylated benzofuran, benzothiophene, and indole derivatives via palladium-catalyzed aryldifluoroalkylation of 1,6-enynes with ethyl difluoroiodoacetate and arylboronic acids has been established. High reaction efficiency, mild conditions, broad substrate scope, and good functional group tolerance are the features of this protocol. Notablely, the resultant products can be smoothly converted into CF2-containing benzofurans, benzothiophenes and indoles through an isomerization process catalyzed by Fe(OTf)3.

In this study, we synthesized four novel Al18/19F-labeled 2-phenylbenzothiazole derivatives conjugated to 1,4,7-triazacyclononane-1,4-diacetic acid via alkyl linkers and evaluated them as imaging agent targets to amyloid-β (Aβ) plaques deposited in the blood vessels of cerebral amyloid angiopathy (CAA) brain. The four ligands exhibited moderate-to-high binding ability to Aβ1–42 aggregates, of which complex 17 possessing the most potent affinity (Ki = 11.3 nM) was selected for further biological evaluations. In vitro fluorescent staining and in vitro autoradiography studies on brain sections from CAA patients proved that this ligand could label Aβ deposits in blood vessels selectively. In biodistribution study, [18F]17 can hardly penetrate the blood–brain barrier (brain2 min = 0.3% ID/g) and displayed a rapid blood washout rate (blood2 min/blood60 min = 25.2), which is favorable as CAA imaging agents. In conclusion, this Al18F-labeled 2-phenylbenzothiazole complex was developed and proved to be a promising...

An oligoethyleneoxy linker was introduced for conjugation between 99mTc/Re-bis(aminoethanethiol) (BAT) and β-amyloid (Aβ) binding scaffolds. Rhenium complexes exhibited high to moderate binding affinity to Aβ1–42 aggregates and efficient fluorescent staining to Aβ plaques in brain tissue. After radiolabeling, the 99mTc-labeled probes revealed improved brain pharmacokinetics in normal ICR mice. Probe [99mTc]15 with potent binding affinity (Ki = 13.4 nM) and the highest initial brain uptake (2.10% ID/g at 2 min) in normal ICR mice was evaluated further. In vitro autoradiography showed specific labeling of Aβ plaques by [99mTc]15 in transgenic (Tg) mouse brain tissue. Ex vivo autoradiography further demonstrated its efficient labeling of Aβ plaques in a living Tg mouse. In vivo single photon emission computed tomography (SPECT)/CT imaging in six rhesus monkeys revealed remarkably improved brain uptakes (1.94–2.63% ID within 20 min) of [99mTc]15, making it highly potential to be used in humans for Aβ plaques ...

Novel D-π-A-π-D probes were investigated for the detection of Aβ plaques and NFTs. The probes displayed remarkable optical properties, and DADNIR-2 possessed high affinity towards Tau and Aβ aggregates (Kd = 0.41 nM and 1.04 nM, respectively) with certain selectivity. DADNIR-2 could penetrate the BBB and label Aβ plaques in vivo.

To expand the scope of D-π-A based near-infrared (NIR) probes for detecting β-amyloid (Aβ) plaques and to systematically explore the relationship among their structural characteristics, optical properties, and biological properties, three series of smart NIR probes with different aromatic rings and up to seven trans double bonds were synthesized and evaluated. Marked correlations between the conjugated π system and properties of these probes, such as optical data, binding ability, and brain uptake, were observed. One probe, PHC-4, displayed improved properties as a NIR probe for the in vivo detection of Aβ plaques.

We have designed and synthesized a series of indole-based σ2 receptor ligands containing 5,6-dimethoxyisoindoline or 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline as pharmacophore. In vitro competition binding assays showed that all ten ligands possessed low nanomolar affinity (Ki=1.79-5.23nM) for σ2 receptors and high subtype selectivity (Ki (σ2)/Ki (σ1)=56-708). Moreover, they showed high selectivity for σ2 receptor over the vesicular acetylcholine transporter (>1000-fold). The corresponding radiotracers [18F]16 and [18F]21 were prepared by an efficient one-pot, two-step reaction sequence with a home-made automated synthesis module, with 10-15% radiochemical yield and radiochemical purity of >99%. Both radiotracers showed high brain uptake and σ2 receptor binding specificity in mice.

A new class of optical isomers of 2-arylbenzofuran derivatives were synthesized and evaluated as potential β-amyloid plaques imaging agents. Both lipophilicity and signal-to-noise ratio were significantly improved by adding a chiral hydroxyl group to 1-fluoro-3-(oxidanyl)propan-2-ol side chain. These derivatives displayed moderate to high binding affinity towards Aβ1-42 aggregates. Four tracers possessing potent binding affinity (Ki < 30 nM) were chosen for further investigation. In in vitro autoradiography studies, the four selected probes showed effective binding to Aβ plaques in Tg mouse and AD human brain tissue after labeled by 18F. The purified enantiomers displayed apparent discrepancy in biodistribution experiments in normal mice, for (S)-enantiomers provided rather faster clearance than (R)-enantiomers. All in all, (S)-[18F]17 (Ki = 14.6 nM) with excellent pharmacokinetics (brain2 min = 8.60% ID/g, brain2 min/brain60 min = 14.1) deserves further evaluation.

Two neutral merocyanine-based near-infrared fluorescent probes were for the first time developed through rational engineering of the classical cationic cyanine scaffold IR-780 for in vivo imaging of amyloid-β plaques. In vivo NIRF imaging revealed that the probe could penetrate the blood-brain barrier and efficiently differentiate the living transgenic and wild-type mice.

Iodo-1,2,3-triazoles are of considerable interest for chemical and biomedical applications. However, current synthetic methods for preparing iodo-1,2,3-triazoles cannot easily be applied to the direct modification of bioactive molecules in water. Through the combination of water-compatible oxidative iodination and the copper-catalyzed alkyne-azide cycloaddition reaction, a novel copper-catalyzed aqueous multicomponent synthetic method for the preparation of 5-iodo-1,2,3-triazoles has been developed. The method is highly effective and selective for substrates including biologically relevant compounds with nucleoside, sugar, and amino acid moieties. Based on this aqueous tandem reaction, a direct single-step multicomponent dual modification of peptide is developed from readily available starting materials. Furthermore, the method could also be applied to concise and fast multicomponent radioactive 125 I labeling from an aqueous solution of commercially available sodium 125 iodide as a starting material.

In this report, we demonstrate that half-curcuminoid could be a better scaffold for PET tracer development. F-CRANAD-101 was designed and found to show significant response to both soluble and insoluble Aβs in the fluorescent spectral tests. PET imaging results indicated that 14 month and 5 month old APP/PS1 AD mice had higher signals in the brain than age-matched wild type mice.

Based on our previous research on the fluorinated phenylquinoxaline scaffold, in this study, different positions of N,N-dimethyl amino group, and alkyl linkers with various lengths were introduced into this scaffold to regulate their lipophilicity and binding affinity to Tau. Four novel 99mTc/Re complexes with diethyl iminodiacetate chelator were synthesized and evaluated as Tau imaging tracers in the brain of Alzheimer's disease. Their specific binding to neurofibrillary tangles was verified by in vitro fluorescence staining and further confirmed by the results of immunofluorescence staining on the same brain sections from AD patient and Tg-tau mice. From in vitro binding assay using recombinant Tau aggregates, complex 4.2 with 6-N(CH3)2 and longer carbon chain (n = 4) displayed the highest affinity (Kd = 59.95 nM). [99mTc]4.2 was achieved by the ligand exchange reaction between dicarboxylic precursor and [99mTc(CO)3(H2O)3]+ intermediate with radiochemical yield over 45%. Ex vivo biodistribution studies on normal ICR mice revealed that [99mTc]4.2 exhibited moderate initial brain uptake (0.61% ID/g) and more structure optimizations are still required to improve the blood-brain barrier permeability.