Molecular Imaging and Biology最新文献

To investigate magnetic relaxation properties of the tailored contrast using paramagnetic gadolinium (Gd) chelates and superparamagnetic iron oxide particles (SPIOs) for cellular magnetic resonance imaging. The study included three different exposed environments with two different characteristic contrast agents which used gadodiamide (Omniscan; Gd-DTPA-BMA) and ferumoxide (Feridex; SPIO) in C6 brain cancer cells. Based on the minimal mutual interaction between these two agents in vitro, we examined the possibility of using mixture of cells that are separately labeled with two contrast agents or using concurrently labeled cells with different concentrations of the two contrast agents. In order to characterize the MR relaxation properties, aqueous solutions containing various concentrations of the two contrast agents were prepared as well as Ficoll solution suspensions containing labeled cells by different labeling schemes and subsequently investigated R₁ and R₂ relaxation rates. The tailored contrast can be created by concurrent labeling of the two contrast agents as well as combining separately labeled cells with the two contrast agents. The proposed method would be applied to generate tailored contrast for efficient detection of magnetically-labeled cells in molecular imaging and cell-based therapy.

Fibrotic diseases are characterized by excessive accumulation of extracellular matrix (ECM) components following tissue injury, ultimately leading to organ dysfunction and failure. The progression of fibrosis is governed by complex molecular signaling pathways, including TGF-β, PDGF, FGF, CTGF, VEGF, and many others, which regulate myofibroblast activation, ECM production, and tissue remodeling. Traditional diagnostic modalities such as magnetic resonance imaging (MRI), computed tomography (CT), and biopsy are limited in their ability to distinguish active fibrogenesis from established fibrosis or detect early molecular changes. Recent advances in molecular imaging such as the development of targeted radiotracers and MRI contrast agents-have enabled more precise detection and characterization of fibrotic processes at both preclinical and clinical levels. The integration of molecular imaging with targeted probes holds promise for improving early diagnosis, guiding therapeutic strategies, and advancing clinical management of fibrosis. This review presents a comprehensive overview of the molecular mechanisms underlying fibrogenesis, highlights key signaling pathways and biomarkers, and discusses current and emerging molecular imaging agents for fibrotic diseases diagnosis and monitoring.

Purpose: This study aimed to elucidate the molecular and genetic factors contributing to negative ⁶⁸Ga-DOTATATE PET imaging in neuroendocrine tumors (NETs). By integrating whole exome sequencing (WES) and single-cell RNA sequencing (scRNA-seq), we sought to unravel the interplay between negative results of ⁶⁸Ga-DOTATATE PET and genetic mutations in NETs.

Methods: A total of 18 patients with lung, ileal, or pancreatic NETs who underwent ⁶⁸Ga-DOTATATE and ¹⁸F-FDG PET/CT scans as part of their initial diagnostic workup were retrospectively reviewed. WES analysis was conducted to investigate the genetic profile of circulating tumor cells of patients with negative ⁶⁸Ga-DOTATATE scans. Leveraging scRNA-seq and single-cell somatic variant calling analysis, we compared the mutation burden and genetic hallmarks of NET cells with high /positive SSTR2 expression to those with negative/low SSTR2 expression.

Results: Our analysis identified an association between negative ⁶⁸Ga-DOTATATE scans and reduced survival rates, regardless of tumor grade. WES highlighted a predominance of missense mutations, including CREBBP mutation, particularly in patients with negative PET results (incidence of %67 vs. %0). We observed a deleterious mutation in the SSTR2, likely accounting for the observed negative PET scans (incidence of %33). Single-cell single nucleotide variant (SNV) analysis showed that the total unique mutation burden in cells with negative/low SSTR2 expression was significantly higher compared to cells with positive/high expression; and notably, the CREBBP mutation was observed in more than 50% of patients and approximately 35% of NET cells. These results indicate that the frequency of CREBBP mutations is nearly as high as other well-known NET mutations such as MEN1, PTEN, and RB1. Additionally, CREBBP mutations are significantly more frequent in tumors with negative/low SSTR2 expression.

Conclusion: This study suggests that CREBBP mutations in NETs may potentially alter SSTR2 expression, indicating that patients with the mutated CREBBP genotype may not be suitable candidates for SSTR2-targeted PET imaging and radionuclide therapy.

Purpose: While PSMA-targeted radioligand therapy (RLT) has shown remarkable efficacy for treating end-stage prostate cancer, the α-emitting RLT often results in severe salivary gland toxicity, limiting its use. Various strategies to mitigate this side effect have been attempted with limited success. Accordingly, this study introduced a new PSMA-targeting ligand with more favorable binding characteristics than the existing ligands.

Procedures: The binding affinity of PSMA-1-DOTA to PSMA was compared with that of PSMA-11 and PSMA I&T. Comparison of uptake in the salivary glands, kidneys and PC3pip tumor cells in the xenograft mouse models between [⁶⁸ Ga]Ga-PSMA-1-DOTA, [⁶⁸ Ga]Ga-PSMA-11 and [⁶⁸ Ga]Ga-PSMA I&T was conducted with microPET/CT within the same week. The same mouse models were treated with [¹⁷⁷Lu]Lu-PSMA-1-DOTA or [¹⁷⁷Lu]Lu-PSMA-617. A compassionate use PET imaging study on a patient with metastatic castration-resistant prostate cancer was performed using [⁶⁸ Ga]Ga-PSMA-1-DOTA.

Results: The binding affinity of PSMA-1-DOTA to PSMA was found to be approximately four times greater than other PSMA-targeted ligands. Imaging with microPET/CT revealed significantly lower kidney, uptake and little salivary and lacrimal gland uptake with [⁶⁸ Ga]Ga-PSMA-1-DOTA compared to other PSMA-radioligands. Preclinical efficacy studies demonstrated that [¹⁷⁷Lu]Lu-PSMA-1-DOTA inhibited tumor growth comparable to that with [¹⁷⁷Lu]Lu-PSMA-617, suggesting its potential to enhance the therapeutic window of targeted RLT by avoiding damage to the salivary glands. The compassionate use PET imaging confirmed the reduced salivary gland uptake of [⁶⁸ Ga]Ga-PSMA-1-DOTA in the patient, indicating its potential utility as a targeting agent for RLT with α- or β-emitting radionuclides in patients with PSMA-positive prostate cancer.

Conclusion: PSMA-1-DOTA shows reduced uptake in salivary glands while effectively targeting PSMA-expressing tumors, thus potentially avoiding the side effects of xerostomia, and possibly moving PSMA-targeted RLT to a more frontline therapy for prostate cancer rather than the current use as a last resort.

Purpose: Since prostate-specific membrane antigen (PSMA) is widely expressed in nearly all stages of prostate cancer (PCa), PSMA tracers can be considered a viable diagnostic tool for PCa. Compared to ⁶⁸Ga-labeled PSMA agents, ¹⁸F-labeled analogues have various advantages, including the ability to achieve large scale production; easy to commercialize due to its longer half-life; and the ability to image late time points. Because [¹⁸F]vinyl sulfone (VS) is a good intermediate for labeling thiol groups in mild conditions with high labeling yield, we explored the use of various VS groups for PSMA modifications in this study.

Procedures: We developed six ¹⁸F-labeled radiotracers targeting PSMA from radioactive intermediates to explore targeting ability and distribution in vivo in LNCaP and 22RV1 tumor-bearing mice. Different labeling methods were compared on their ability to lead to PSMA agents with high contrast and uptake.

Results: In vitro stability assay showed that the tracer [¹⁸F]4a had high stability, with more than 95% of the radiochemical purities remaining as intact forms after 0.5, 1, and 2 h incubation, respectively. In vitro binding assays showed that [¹⁸F]4a has a low-micromole binding affinity of 9.45 µM. Cell uptake and internalization assays found that [¹⁸F]4a exhibited the highest cell uptake and internalization in 22RV1 cells (1.25 ± 0.06, 1.32 ± 0.11, 1.73 ± 0.08, and 2.03 ± 0.14%ID/10⁶ cells after 10 min, 30 min, 1 h, and 2 h incubation, respectively for cell uptake assay; 0.52 ± 0.02, 0.70 ± 0.11, 0.78 ± 0.04, and 0.98 ± 0.15%ID/10⁶ cells after 10 min, 30 min, 1 h, and 2 h incubation, respectively for cell internalization assay.) Analysis of the PET images showed that the tracer [¹⁸F]4a had the highest tumor uptake (3.38 ± 0.35%ID/g at 2 h p. i. in 22RV1 tumor-bearing mice; 30.16 ± 13.00%ID/g at 2 h p. i. in LNCaP tumor-bearing mice.) Of note, the tracer [¹⁸F]4a showed an approximately threefold increase in tumor uptake compared to [⁶⁸Ga]PSMA-11 in LNCaP tumor-bearing mice at 2 h p. i. The biodistribution experiment verified the accuracy of the in vivo distribution of [¹⁸F]4a in LNCaP and 22RV1 tumor-bearing mice by PET/CT imaging.

Conclusions: PSMA-targeted radiotracer [¹⁸F]4a is a promising PET agent for prostate cancer diagnosis.

Purpose: Prostate-specific membrane antigen-targeted radioligand therapy (PSMA-RLT) is a promising approach to treating metastatic castration-resistant prostate cancer (mCRPC). With the emergence of oxalyldiaminopropionic acid urea (ODAP-Urea) based radioligands targeting PSMA, novel paradigms focused on PSMA-RLT are garnering attention. This study aims to assess potentially novel ODAP-Urea-based radioligands prepared for PSMA-RLT.

Methods: Albumin binding moieties (ABMs) were selected for optimization. Candidates were evaluated in vitro and subsequently investigated through biodistribution and imaging studies in 22Rv1 tumor-bearing mice.

Results: We synthesized five novel ODAP-Urea-based derivatives (CXY-18, CXY-19, CXY-20, CXY-21, CXY-23) with specific ABM. All compounds demonstrated high affinities for PSMA (K_i values ranging from 0.21 nM to 3.6 nM) and strong human albumin protein binding abilities (83.4 ± 1.6% to 94.6 ± 0.4%). [⁶⁸Ga]Ga-CXY-18 (CXY-18) PET/CT exhibited the highest tumor uptake and blood retention properties. Moreover, the internalization of [⁶⁸Ga]Ga-CXY-18 in the 22Rv1 cell line (23.81 ± 1.67%) exceeded that of [⁶⁸Ga]Ga-PSMA-617 (9.99 ± 0.98%). Biodistribution studies confirmed prolonged blood retention and enhanced tumor uptake with [¹⁷⁷Lu]Lu-CXY-18, peaking at 48 h post-injection (4 h: 27.22 ± 3.61%ID/g; 24 h: 30.61 ± 4.96%ID/g; 48 h: 33.92 ± 2.98%ID/g; 96 h: 30.97 ± 1.87%ID/g; 192 h: 9.03 ± 3.49%ID/g).

Conclusion: Our study indicates that CXY-18 possesses high PSMA specificity and tumor uptake, underscoring its promising potential for PSMA-RLT using 4-IBA.

Purpose: To assess alterations in H3R availability with age and body mass index (BMI) in healthy humans using in vivo [¹¹C]GSK189254 positron emission tomography (PET) imaging.

Procedure: Twenty-four healthy individuals (2 females, 22 males; age range 20-47 years) were scanned with [¹¹C]GSK189254 with High-Resolution Research Tomograph (HRRT) or HR plus scanner. Regional V_T (volume of distribution) values were computed using the two-tissue compartment model. The correlation between V_T and age, BMI were examined, adjusting for relevant potential confounding effects of age or gender and injected mass.

Results: H3R availability (V_T) was correlated with age but not BMI. V_T displayed a negative correlation with age in the anterior cingulate cortex (r = -0.61, p = 0.004), frontal cortex (r = -0.50, p = 0.020), olfactory cortex (r = -0.50, p = 0.022), parietal cortex (r = -0.58, p = 0.006), cerebellum cortex (r = -0.53, p = 0.013), insula (r = -0.48, p = 0.027), putamen (r = -0.46, p = 0.034), thalamus (r = -0.45, p = 0.038), and hippocampus (r = 0.45, p = 0.039).

Conclusion: This in vivo H3R study found a significant age-related decline in most cortical and subcortical regions.

Purpose: Malignant melanoma is a highly lethal malignancy typically characterized by the expression of melanin, which is an attractive diagnostic and therapeutic target in these cancers because it is expressed in few other tissues. Following preclinical evaluation of the melanin-targeting PET tracer, [18F]-6-fluoro-N-[2-(diethylamino)ethyl] pyridine-3-carboxamide ([18F]MEL050), we sought to evaluate this agent in patients with melanoma.

Method: A phase I clinical trial was performed in ten patients with metastatic melanoma. Safety, dosimetry and diagnostic performance of intravenously administered][18F]MEL050 were evaluated. Based on results from this trial, we further assessed the prevalence and prognostic significance of loss of melanin expression in two historical patient cohorts for which there were matching histological and clinical outcome data.

Results: Across the trial cohort, no adverse safety signals resulted from [18F]MEL050 administration. The whole-body effective dose was 0.0163 mSV/MBq for an adult male and 0.0206 mSV/MBq for an adult female. The human biodistribution was favorable with low uptake in organs at high risk of metastatic spread, including the brain. Of metastatic sites identified as melanoma on [18F]FDG PET/CT, only 31/65 (48%) were positive on [18F]MEL050 PET. Four [18F]FDG+[18F]MEL050+ metastases were resected from three patients and found to be melanotic by histological examination, whereas five [18F]FDG+[18F]MEL050- metastases from two patients were amelanotic. In our historical cohorts, amelanosis was more common in metastatic than primary disease (45% versus 20%) and the presence of melanin within sentinel lymph node metastases was associated with worse disease-free (HR 2.3 95% CI 1.3 - 4.3, p = 0.002) and disease-specific survivals (HR 3.6, 95% CI 1.4 - 9.7,p = 0.009) in stage III disease, compared with amelanotic sentinel lymph node metastases.

Conclusion: We propose caution in the use of melanin-targeted agents for melanoma diagnosis and therapy until their utility as prognostic or predictive imaging biomarkers, and the biological implications of loss of melanin deposition during melanoma progression, are better understood.

Purpose: This study aimed to evaluate the feasibility and diagnostic utility of a dual-target positron emission tomography (PET) imaging approach using a cocktail of N-3-[¹⁸F]fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane ([¹⁸F]FP-CIT) and [¹⁸F]florbetaben (FBB) for the simultaneous assessment of dopaminergic and amyloid changes in a preclinical setting.

Procedures: We utilized both Parkinson's disease (PD) and Alzheimer's disease (AD) mouse models, as well as a control group, to investigate the uptake of [¹⁸F]FP-CIT and [¹⁸F]FBB individually and in combination. PET imaging was conducted, and standardized uptake value ratios (SUVRs) were analyzed for each model across the striatal and cortical regions. Comparisons were made between single and cocktail PET scans to assess potential cross-interference of the tracers.

Results: In both PD and AD models, no statistically significant differences were observed in the SUVRs between single-tracer and cocktail PET scans in the striatum and cortex (p > 0.4 for striatal comparisons, p > 0.8 for cortical comparisons). Bland-Altman analysis showed no significant bias, supporting the interchangeability of SUVRs between single and cocktail PET scans.

Conclusions: This preclinical study suggests that [¹⁸F]FP-CIT and [¹⁸F]FBB PET imaging is a viable dual-target imaging approach for neurodegenerative disease evaluation. The method could streamline diagnostic workflows and improve patient convenience. Further clinical studies are warranted to validate the efficacy and safety of this approach in human populations.

Purpose: This study aimed to evaluate the diagnostic value of [¹⁸F]-FDG PET/MRI for the diagnosis of neck lymph node metastasis (LNM) in patients with initially diagnosed papillary thyroid cancer (PTC) and to compare it with [⁶⁸ Ga]-FAPI-04 PET/MRI.

Methods: Thirty patients with PTC confirmed by thyroid fine-needle aspiration biopsy were prospectively enrolled and underwent [¹⁸F]-FDG PET/MRI; of which, 6 additionally underwent [⁶⁸ Ga]-FAPI-04 PET/MRI within 3 days. According to surgical guidelines, the neck lymph node (LN) was divided into three macroscopic regions: central (VI) and left/right lateral neck (II-V). Images were semi-quantitatively and visually interpreted, and lesions' quantity, location, and uptake values were noted. Diagnostic performance of [¹⁸F]-FDG PET/MRI versus US and MRI in N-staging of PTC patients based on regional analysis using postoperative histopathology as the gold standard. Whether the BRAF_V600E mutation or not affects metastatic LN radioactivity uptake. Exploring the relevance of dual tracer imaging of metastatic LN radioactivity uptake and its head-to-head comparison for diagnostic efficacy.

Results: A total of 48 macroscopic regions were surgically dissected. In terms of predicting LNM, the diagnostic efficacy of [¹⁸F]-FDG PET/MRI for detecting LNM was higher than that of US and MRI, overall sensitivity, specificity, and accuracy were 71.1% vs. 60.5% vs. 65.8%, 90.0% vs.80.0% vs. 80.0%, and 75.0% vs. 64.6% vs. 68.8%, respectively (all P > 0.05). SUV_max of metastatic LNs on [⁶⁸ Ga]-FAPI-04 PET/MRI was positively correlated with [¹⁸F]-FDG PET/MRI (r = 0.8564, 95%CI: 0.7208-0.9289; P < 0.0001). BRAF_V600E mutation had no significant effect on the [¹⁸F]-FDG uptake level and TBR value in metastatic LN of PTC (SUV_max: 2.5 ± 2.3 vs. 2.2 ± 1.1; TBR: 2.9 ± 2.6 vs. 2.6 ± 1.4; all P > 0.05). The positive lesion detection rate of dual tracer imaging in 6 patients with PTC is consistent, and the degree of radioactivity uptake of [⁶⁸ Ga]-FAPI-04 was higher than that of [¹⁸F]-FDG in both primary lesion and LNM (12.3 ± 5.7 vs. 6.9 ± 5.3;4.5 ± 3.7 vs. 3.4 ± 1.8; all P > 0.05).

Conclusion: [¹⁸F]-FDG PET/MRI demonstrated marginally superior diagnostic performance for LNM detection compared to US and MRI, but all three modalities exhibited suboptimal sensitivity, particularly in the central region. Small sample populations revealed no significant differences in [⁶⁸ Ga]-FAPI-04 and [¹⁸F]-FDG uptake levels in primary lesion and LNM of PTC, but relatively lower nonspecific uptake of [⁶⁸ Ga]-FAPI-04 pharyngeal lymphatic ring may have the potential to reduce diagnostic error in specific diseases.