Xianzhong Zhang

The accurate discrimination of bacterial infections from sterile inflammation is a critical yet unresolved challenge in clinical diagnostics. To address this, we designed and synthesized a series of 68Ga-labeled PET tracers derived from the FDA-approved iron chelator, deferasirox. The probes, denoted [68Ga]Ga-DFC2D, [68Ga]Ga-DFA2D, and [68Ga]Ga-DFA3D, were systematically evaluated for their Fe(III) chelation ability, stability, and bacteria-binding selectivity. In a murine model of bacterial myositis, [68Ga]Ga-DFA2D emerged as the lead candidate, demonstrating optimal pharmacokinetics and, most importantly, a remarkable ability to clearly differentiate bacterial infection from sterile inflammation. Preliminary mechanistic studies suggest that the exceptional targeting specificity of [68Ga]Ga-DFA2D may be attributed to its unique ability to form an iron-probe-MurB interaction mechanism, enhancing its uptake with bacterial targets. This work establishes a novel and robust strategy for developing bacteria-specific PET tracers, paving the way for the precise diagnosis and management of bacterial infections.

PSMA is an attractive theranostic target for prostate cancer (PCa). Inspired by the oral absorption enhancer SNAC, we report a novel strategy for optimizing PSMA-targeted radioligands via covalent SNAC conjugation distinct from conventional albumin-binding designs. Three SNAC-modified ligands (PSA3-1, PDA3-1, PDB3-1) bearing quinoline/naphthalene linkers were radiolabeled with ⁶⁸Ga and ¹⁷⁷Lu, affording high radiochemical purity (>98%) and hydrophilicity. PDB3-1 displayed the highest PSMA binding affinity (IC₅₀ = 19.1 nM; docking score: -12.3 kcal/mol). In PC-3 PIP tumor-bearing mice, [⁶⁸Ga]Ga-PDB3-1 PET revealed high tumor uptake with minimal background. Corresponding [¹⁷⁷Lu]Lu-PDB3-1 biodistribution studies confirmed low systemic retention and rapid renal clearance. Therapy [¹⁷⁷Lu]Lu-PDB3-1 achieved tumor inhibition and survival benefits comparable to [¹⁷⁷Lu]Lu-PSMA-617, even at a reduced dose (9.25 MBq). High-tolerated dose studies (111 MBq) confirmed safety with unremarkable histopathology. These findings suggest that SNAC conjugation may represent a promising approach for the development of PSMA-targeted radiotheranostics for PCa.

Integrated diagnostic and therapeutic nuclear medicine requires chelators that coordinate multiple radionuclides efficiently under mild conditions. Herein, we developed H₄pyox, an acyclic chelator with a preorganized cavity designed to balance rapid kinetics with a high thermodynamic stability. H₄pyox achieves roughly quantitative radiochemical yields with various diagnostic and therapeutic radionuclides, ⁶⁸Ga, ⁸⁶Y, ¹⁷⁷Lu, etc., within 10 min at ambient temperature, whereas DOTA requires heating (>90 °C). Notably, H₄pyox maintains an ∼100% yield for ¹⁷⁷Lu at concentrations as low as 10^-7 M, significantly outperforming DOTA. To facilitate clinical translation, an activated ester, H₄pyox-NHS, was synthesized for efficient bioconjugation. The [¹⁷⁷Lu]Lu-pyox complex showed excellent stability in saline and mouse serum over 7 days of incubation, which is comparable to that of the [¹⁷⁷Lu]Lu-DOTA complex. Density functional theory calculations revealed that structural preorganization and high donor nucleophilicity underpin its rapid kinetics. Moreover, in vivo single-photon emission computed tomography/computed tomography imaging confirmed the stability of the [¹⁷⁷Lu]Lu-pyox complex and a dual metabolic excretion pathway (renal/hepatobiliary) without bone accumulation. These results support the potential of H₄pyox for radiopharmaceutical development and provide a complementary choice in the design of metal-based radiopharmaceuticals and in the tuning of their pharmacokinetic properties─especially for targeting vectors with poor thermal stability.

Prostate-specific membrane antigen (PSMA) is highly overexpressed in prostate cancer, making it an effective diagnostic biomarker and therapeutic target for PCa. However, many PSMA-targeted small-molecule probes suffer from suboptimal tumor uptake and retention. In this study, a series of PSMA ligands were rationally designed and synthesized using classical lipidation and fatty acid modification strategies, and subsequently labeled with ⁶⁸Ga/¹⁷⁷Lu to address these limitations. Cellular studies and molecular docking simulations confirmed their PSMA specificity and protein-binding properties. In a PC-3 PIP xenograft mouse model, nine ⁶⁸Ga-labeled PSMA-targeted radioligands were evaluated using PET imaging. Among them, [⁶⁸Ga]Ga-PDA2-C6 and [⁶⁸Ga]Ga-PDA1-1 demonstrated remarkable tumor accumulation and retention, with improved tumor-to-nontarget (T/NT) ratios. Biodistribution studies further revealed pronounced tumor retention of [¹⁷⁷Lu]Lu-PDA2-C6 and [¹⁷⁷Lu]Lu-PDA1-1. Overall, this proof-of-concept study validated that conjugating PSMA ligands with tailor-made lipid chain and fatty acids can markedly enhance tumor uptake and retention while maintaining a low level of kidney retention.

Tumor hypoxia is a major contributor to therapeutic resistance, including radio-, chemo-, and immunotherapy, and is closely linked to unfavorable clinical outcomes. PET imaging has shown promise in guiding the clinical treatment of hypoxic tumors. Here, we developed an NTR-responsive PET strategy for in vivo tumor hypoxia imaging using radiolabeled nitrogen mustard analogues (¹⁸F-NTRP and ¹⁸F-NCRP). Cell uptake studies with A549 cells showed that ¹⁸F-NTRP and ¹⁸F-NCRP exhibited approximately two fold higher uptake and good retention under hypoxic conditions. MicroPET imaging of A549 tumor-bearing mice revealed pronounced tumor accumulation of both ¹⁸F-NTRP and ¹⁸F-NCRP, with uptake values of 1.95 ± 0.37 and 2.86 ± 0.49 %ID/g, respectively, and a rapid clearance rate in normal organs. At 45 min postinjection, the tumor/muscle (T/M) ratios of ¹⁸F-NTRP and ¹⁸F-NCRP were 2.62 and 3.44, respectively, both substantially higher than that of ¹⁸F-FMISO (1.40, p < 0.05). Following dicoumarin-mediated inhibition of tumor NTR, the uptake and T/M ratio of ¹⁸F-NCRP were decreased to 1.25 ± 0.32 %ID/g and 1.26 (p < 0.001), respectively. Moreover, T/M ratios correlated well with HIF-1α (r² = 0.71) and NTR (r² = 0.66) levels in the A549 tumor. Collectively, PET imaging demonstrated that ¹⁸F-NCRP specifically targets tumor NTR and can potentially discriminate between varying degrees of hypoxia.

Hydrogen peroxide (H₂O₂), a key reactive oxygen species, is overexpressed in metabolically dysregulated cells and involved in various disease processes. Herein, we present a class of organochalcogen-based complexes that serve as ¹⁹F MRI probes for H₂O₂ detection by exhibiting large ¹⁹F chemical-shift changes upon oxidation. Designed probes based on trifluoromethylselenide (CF₃Se^-) and trifluoromethyltelluride (CF₃Te^-) react rapidly with H₂O₂ under mild reaction conditions. The corresponding ¹⁹F chemical-shift changes reach up to 28 and 55 ppm, respectively, under our experimental settings. These substantial shift ranges enable ¹⁹F chemical-shift-switching MRI to specifically visualize H₂O₂-rich regions. Notably, the ¹⁹F MRI results of the Se-based analogue demonstrate that a detectable chemical-shift range can be achieved at biologically relevant H₂O₂ concentrations in a living mouse model of hind limb inflammation. This proof-of-concept study highlights the feasibility of constructing a visual imaging platform using organochalcogen-based ¹⁹F MRI probes with large chemical-shift responsiveness.

Accumulation in nontarget tissues, particularly the salivary glands, remains a major challenge for prostate-specific membrane antigen (PSMA)-targeted radiotherapeutics, narrowing the theranostic window. In this work, we developed quinoline/naphthalene-derived PSMA radiotracers ([¹⁸F]AlF-NNA₈P₁, [¹⁸F]AlF-NNB₈P₁, and [¹⁸F]AlF-NCB₈P₁) to minimize nontarget accumulation through systematic molecular optimization. All probes exhibited excellent stability in vitro and in vivo. In PSMA-positive PC3-PIP cells, a significant uptake was observed with nanomolar binding affinities. Visual drug screening and first-in-human studies were conducted. In PSMA-positive tumor models, micro-positron emission tomography (PET) imaging and biodistribution demonstrated high tumor uptake, significantly blocked by coinjection with PSMA inhibitors. The probes showed blood clearance primarily and a low background retention. In initial clinical evaluations, [¹⁸F]AlF-NCB₈P₁ outperformed the widely used [¹⁸F]PSMA-1007, enabling clear visualization of metastatic lesions. The preclinical and clinical results validate that these quinoline/naphthalene-based radiotracers hold promise for enriching the prostate cancer (PCa) precision oncology toolkit, paving the way for next-generation theranostic agents with improved precision and safety.

Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is highly upregulated in multiple cancers and serves as a promising biomarker for patient staging and therapy guidance. We designed five ROR1-targeted radiotracers, including linear and cyclic peptides derived from PR7, and evaluated their specificity and affinity in vitro and in vivo. All probes showed a rapid tumor uptake within 30 min in MC38 models. Saturation binding assays and blocking studies confirmed the ROR1 specificity. Positron emission tomography imaging with [68Ga]Ga-DP1 and [18F]AlF-NP1 demonstrated excellent tumor targeting and favorable target-to-nontarget ratios across multiple models, with renal clearance observed in biodistribution. Transcriptomic analysis indicated the potential involvement of ROR1 in the PI3K/AKT pathway. In general, these findings support [18F]AlF-NP1 and [68Ga]Ga-DP1 as promising noninvasive imaging agents for quantitative ROR1 visualization and personalized cancer therapy.