Hongjun Jin

Background: Tumor necrosis factor receptor 2 (TNFR2) is a pivotal immune checkpoint that is highly expressed within the immunosuppressive tumor microenvironment (TME), particularly on regulatory T cells (Tregs). The P20 peptide specifically binds TNFR2, but its rapid enzymatic degradation in vivo severely limits its clinical translation as an imaging tracer. Methods: Here, we developed a P20-conjugated lipid nanoprobe (DPP) via thin-film hydration and systematically evaluated its physicochemical properties, receptor-binding specificity, biosafety, and in vivo positron emission tomography (PET)/computed tomography (CT) imaging performance in male C57BL/6J mice bearing subcutaneous MC38 wild-type (WT) or TNFR2-knockout (KO) colon tumors. Results: DPP exhibited a near-spherical morphology, a predominant particle-size distribution peak at approximately 125.6 nm, a negative surface charge, and relatively stable hydrodynamic diameters over 7 days. In vitro assays supported TNFR2-associated cellular recognition and showed negligible cytotoxicity under the tested conditions. Micro-PET/CT imaging revealed that DPP markedly improved tumor retention (tumor SUVmean at 4 h: 0.577 ± 0.314) compared with free P20 (SUVmean at 4 h: 0.065 ± 0.011; n = 6 per group; two-sided Welch’s unpaired t-test with Benjamini–Hochberg correction, adjusted q = 0.010298) in MC38-WT tumors. Tumor SUVmean was higher in WT than in KO tumors at 7 h (0.677 ± 0.181 vs. 0.381 ± 0.191; p = 0.02942) and 12 h (0.428 ± 0.121 vs. 0.224 ± 0.108; p = 0.01588), with both adjusted q values equal to 0.05885 (n = 6 and n = 5, respectively). Notably, tumor-to-muscle uptake ratios were also higher in WT tumors at 7 h (13.11 ± 5.10 vs. 6.86 ± 2.97; p = 0.03459; adjusted q = 0.13836). Conclusions: These results demonstrate that the liposomal formulation enhances tumor-associated uptake of the P20-based tracer, while TNFR2-dependent uptake and the non-invasive monitoring of Treg compartments remain to be validated.

Proliferating cell nuclear antigen (PCNA) is a central regulator of glioma stem cell maintenance and therapy resistance, yet no noninvasive method exists to visualize its expression in vivo. We developed [18F]FPON, a first-in-class small-molecule PET tracer targeting PCNA, derived from the clinical inhibitor AOH1996. FPON binds recombinant PCNA with a Kd of 900.8 ± 131.2 nM, comparable to AOH1996. [18F]FPON is synthesized in one step with a decay-corrected radiochemical yield of 11.43 ± 4.03% (n = 6) and >95% radiochemical purity, readily crosses the blood−brain barrier, and remains >87% intact in brain at 60 min post-injection. In orthotopic U87 glioma xenografts, [18F]FPON exhibits specific tumor uptake (SUVr = 2.58 ± 0.38 vs contralateral brain), which is significantly reduced by AOH1996 (SUVr = 1.62 ± 0.24, p < 0.01). These results establish [18F]FPON as a promising PET tracer for noninvasive imaging of PCNA and support its potential use as a companion diagnostic for PCNA-targeted therapies.

Neuroinflammation is a central pathological process underlying neurodegenerative diseases, including Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis. Positron emission tomography (PET) molecular probes now enable the noninvasive, quantitative visualization of neuroinflammatory processes in the living brain. This review surveys recent advances in PET probes targeting microglial activation markers─including the 18 kDa translocator protein (TSPO), the purinergic P2X7 receptor (P2X7R), colony-stimulating factor 1 receptor (CSF1R), and sphingosine-1-phosphate receptor 1 (S1PR1)─as well as astrocyte reactivity markers such as monoamine oxidase B (MAO-B) and imidazoline-2 binding sites (I2BS). I discuss the evolution from first-generation TSPO ligands to polymorphism-insensitive third-generation tracers, highlight emerging targets beyond TSPO, and evaluate the translational value of these probes for early diagnosis, disease staging, treatment monitoring, and drug development. Current challenges-including limited cellular specificity, genetic polymorphism effects, quantification difficulties, and clinical accessibility barriers─are analyzed alongside promising solutions. Integrating neuroinflammation PET into multimodal biomarker frameworks will be essential for advancing precision medicine in neurodegenerative diseases.

Increasing evidence of the role of neuroinflammation in pathophysiology has highlighted the importance of P2X7 receptor (P2X7R)-targeted neurodegeneration

P2 × 7 receptor (P2 × 7R) represents a promising therapeutic target for Alzheimer's disease (AD), given its marked upregulation in neuroinflammation and involvement in amyloid-β (Aβ) and tau pathology. Although several P2 × 7R antagonists with high central nervous system (CNS) penetration and cross-species activity have been developed, none have yet reached clinical use, underscoring the need for optimized agents suitable for chronic neurological conditions. In this study, we designed a series of brominated P2 × 7R antagonists based on a prominent antagonist Lu AF27139, among which the lead compound YH1 exhibited favorable lipophilicity, brain penetration, plasma stability, and receptor binding. In transgenic AD mice, YH1 treatment significantly alleviated cognitive deficits, reduced cerebral P2 × 7R expression, and decreased Aβ load. Using ¹⁸F-GSK1482160 positron emission tomography (PET) imaging, we observed a significant decline of P2 × 7R binding, indicating that YH1-mediated cognitive improvement involves targeted suppression of P2 × 7R-driven neuroinflammation. These results establish a precision AD-oriented optimization of the Lu AF27139 scaffold, demonstrate measurable PK improvements, and provide the first PET-verified P2 × 7R target engagement in an AD model, supporting translational relevance.

To investigate the role of cholinergic neuronal activity in Parkinson's disease (PD), A53T transgenic mice underwent [ ¹⁸ F]VAT PET imaging targeting the vesicular acetylcholine transporter. Baseline scans revealed cholinergic hyperactivity in multiple brain regions including amygdala, basal forebrain septum, cortex, hippocampus, hypothalamus, midbrain, striatum and thalamus, while [ ¹⁸ F]L-DOPA PET indicated dopaminergic neuron loss in the striatum. After five weeks of montelukast treatment, motor function improved, accompanied by significantly reduced [ ¹⁸ F]VAT binding in above brain regions and increased [ ¹⁸ F]L-DOPA uptake only in the striatum. [ ¹⁸ F]VAT uptake in the hippocampus positively correlated with motor recovery including muscle strength deficits, coordination impairments, and endurance limitations. These results suggest that cholinergic modulation improves motor deficits in PD, and [ ¹⁸ F]VAT PET represents a promising tool for monitoring cholinergic responses.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation. This study aimed to use the sphingosine 1-phosphate receptor 1 (S1PR1) targeted tracer [¹⁸F]TZ4877 with PET/CT to assess synovial inflammation in a collagen-induced arthritis (CIA) mouse model. [¹⁸F]TZ4877 and [¹⁸F]FDG PET/CT imaging were performed on RA (n = 6) and control (n = 6) mice. The Logan kinetic model with a graphical arterial input function analysis was used to quantitatively evaluate the in vivo expression of S1PR1. Histological and immunofluorescence (IF) staining were performed postimaging. The relationship between fibroblast-like synoviocyte (FLS) expression and [¹⁸F]TZ4877 uptake was also analyzed. [¹⁸F]TZ4877 uptake was significantly higher in CIA mice than in controls and positively correlated with arthritis scores (r = 0.876, p < 0.001). The specific binding potential (BP_ND) values of [¹⁸F]TZ4877 in the hindfoot joints of the RA group (1.33 ± 0.23) were greater than those in the control group (0.14 ± 0.04). In contrast, there was no significant difference in the [¹⁸F]FDG uptake between the two groups. IF staining demonstrated the colocalization of S1PR1 with FLS in the hindfoot joints of CIA mice. Quantitative analysis indicated that in areas with greater numbers of FLSs, the expression of S1PR1 was correspondingly increased. In PET/CT imaging of RA, [¹⁸F]TZ4877 can be used to detect the expression of S1PR1 effectively in CIA mouse models. The radiotracer holds promise as a noninvasive tool for the quantitative diagnosis of RA.

Neuroinflammation is a key factor in Parkinson's disease (PD) pathogenesis. However, the regional heterogeneity of biomarkers related to inflammation in PD is less well defined. We developed [¹⁸F]GSK PET imaging to quantify neuroinflammation via the P2X7 receptor (P2X7R) in A53T PD male mice and wild-type (WT) male mice. Montelukast (MK) was administered to mice, and weekly behavior tests confirmed MK's efficacy. [¹⁸F]L-DOPA/[¹⁸F]GSK PET, motor testing, autoradiography, and immunofluorescence were performed after MK treatments. MK improved motor function and reduced the brain uptake of [¹⁸F]GSK, indicating resynchronization of regional microglial activity. The whole brain uptake of [¹⁸F]GSK was correlated with motor functional restoration, while [¹⁸F]L-DOPA PET was not. Overall, our study indicated that brain mapping of [¹⁸F]GSK PET is beneficial for exploring P2X7R-related neuroinflammation, which is correspondent to motor function in PD.