EJNMMI Research最新文献

Background: We designed and synthesized a novel bisphosphonate radiopharmaceutical (⁶⁸ Ga- or ¹⁷⁷Lu-labeled DOTA-ibandronate [⁶⁸ Ga/¹⁷⁷Lu-DOTA-IBA]) for the targeted diagnosis and treatment of bone metastases. The biodistribution and internal dosimetry of a single therapeutic dose of ¹⁷⁷Lu-DOTA-IBA were evaluated using a series of single-photon emission computerized tomography (SPECT) images and blood samples. Five patients with multiple bone metastases were included in this prospective study. After receiving 1110 MBq ¹⁷⁷Lu-DOTA-IBA, patients underwent whole-body planar, SPECT/CT imaging and venous blood sampling over 7 days. Dosimetric evaluation was performed for the main organs and tumor lesions. Safety was assessed using blood biomarkers.

Results: ¹⁷⁷Lu-DOTA-IBA showed fast uptake, high retention in bone lesions, and rapid clearance from the bloodstream in all patients. In this cohort, the average absorbed doses (ADs) in the bone tumor lesions, kidneys, liver, spleen, red marrow, bladder-wall, and osteogenic cells were 5.740, 0.114, 0.095, 0.121, 0.095, and 0.333 Gy/GBq, respectively. Although no patient reached the predetermined dose thresholds, the red marrow will be the dose-limiting organ. There were no adverse reactions recorded after the administration of 1110 MBq ¹⁷⁷Lu-DOTA-IBA.

Conclusion: Dosimetric results show that the ADs for critical organs and total body are within the safety limit and with high bone retention. It is a promising radiopharmaceutical alternative for the targeted treatment of bone metastases, controlling its progression, and improving the survival and quality of life of patients with advanced bone metastasis.

Background: Cancer stem cells play an important role in driving tumor growth and treatment resistance, which makes them a promising therapeutic target to prevent cancer recurrence. Emerging cancer stem cell-targeted therapies would benefit from companion diagnostic imaging probes to aid in patient selection and monitoring response to therapy. To this end, zirconium-89-radiolabeled immunoPET probes that target the cancer stem cell-antigen CD133 were developed using fully human antibody and antibody scFv-Fc scaffolds.

Results: ImmunoPET probes [⁸⁹Zr]-DFO-RW03_IgG (CA = 0.7 ± 0.1), [⁸⁹Zr]-DFO-RW03_IgG (CA = 3.0 ± 0.3), and [⁸⁹Zr]-DFO-RW03_{scFv - Fc} (CA = 2.9 ± 0.3) were radiolabeled with zirconium-89 (radiochemical yield 42 ± 5%, 97 ± 2%, 86 ± 12%, respectively) and each was isolated in > 97% radiochemical purity with specific activities of 120 ± 30, 270 ± 90, and 200 ± 60 MBq/mg, respectively. In vitro binding assays showed a low-nanomolar binding affinity of 0.6 to 1.1 nM (95% CI) for DFO-RW03_IgG (CA = 0.7 ± 0.1), 0.3 to 1.9 nM (95% CI) for DFO-RW03_IgG (CA = 3.0 ± 0.3), and 1.5 to 3.3 nM (95% CI) for DFO-RW03_{scFv - Fc} (C/A = 0.3). Biodistribution studies found that [⁸⁹Zr]-DFO-RW03_{scFv - Fc} (CA = 2.9 ± 0.3) exhibited the highest tumor uptake (23 ± 4, 21 ± 2, and 23 ± 4%ID/g at 24, 48, and 72 h, respectively) and showed low uptake (< 6%ID/g) in all off-target organs at each timepoint (24, 48, and 72 h). Comparatively, [⁸⁹Zr]-DFO-RW03_IgG (CA = 0.7 ± 0.1) and [⁸⁹Zr]-DFO-RW03_IgG (CA = 3.0 ± 0.3) both reached maximum tumor uptake (16 ± 3%ID/g and 16 ± 2%ID/g, respectively) at 96 h p.i. and showed higher liver uptake (10.2 ± 3%ID/g and 15 ± 3%ID/g, respectively) at that timepoint. Region of interest analysis to assess PET images of mice administered [⁸⁹Zr]-DFO-RW03_{scFv - Fc} (CA = 2.9 ± 0.3) showed that this probe reached a maximum tumor uptake of 22 ± 1%ID/cc at 96 h, providing a tumor-to-liver ratio that exceeded 1:1 at 48 h p.i. Antibody-antigen mediated tumor uptake was demonstrated through biodistribution and PET imaging studies, where for each probe, co-injection of excess unlabeled RW03_IgG resulted in > 60% reduced tumor uptake.

Conclusions: Fully human CD133-targeted immunoPET probes [⁸⁹Zr]-DFO-RW03_IgG and [⁸⁹Zr]-DFO-RW03_{scFv - Fc} accumulate in CD133-expressing tumors to enable their delineation through PET imaging. Having identified [⁸⁹Zr]-DFO-RW03_{scFv - Fc} (CA = 2.9 ± 0.3) as the most attractive construct for CD133-expressing tumor delineation, the next step is to evaluate this probe using patient-derived tumor models to test its detection limit prior to clinical translation.

Background: Neuropsychiatric sequelae of COVID-19 have been widely documented in patients with severe neurological symptoms during the chronic or subacute phase of the disease. However, it remains unclear whether subclinical changes in brain metabolism can occur early in the acute phase of the disease. The aim of this study was to identify and quantify changes in brain metabolism in patients hospitalized for acute respiratory syndrome due to COVID-19 with no or mild neurological symptoms.

Results: Twenty-three non-intubated patients (13 women; mean age 55.5 ± 12.1 years) hospitalized with positive nasopharyngeal swab test (RT-PCR) for COVID-19, requiring supplemental oxygen and no or mild neurological symptoms were studied. Serum C-reactive protein measured at admission ranged from 6.43 to 189.0 mg/L (mean: 96.9 ± 54.2 mg/L). The mean supplemental oxygen demand was 2.9 ± 1.4 L/min. [¹⁸F]FDG PET/CT images were acquired with a median of 12 (4-20) days of symptoms. After visual interpretation of the images, semiquantitative analysis of [¹⁸F]FDG uptake in multiple brain regions was evaluated using dedicated software and the standard deviation (SD) of brain uptake in each region was automatically calculated in comparison with reference values of a normal database. Evolutionarily ancient structures showed positive SD mean values of [¹⁸F]FDG uptake. Lenticular nuclei were bilaterally hypermetabolic (> 2 SD) in 21/23 (91.3%) patients, and thalamus in 16/23 (69.6%), bilaterally in 11/23 (47.8%). About half of patients showed hypermetabolism in brainstems, 40% in hippocampi, and 30% in cerebellums. In contrast, neocortical regions (frontal, parietal, temporal and occipital lobes) presented negative SD mean values of [¹⁸F]FDG uptake and hypometabolism (< 2 SD) was observed in up to a third of patients. Associations were found between hypoxia, inflammation, coagulation markers, and [¹⁸F]FDG uptake in various brain structures.

Conclusions: Brain metabolism is clearly affected during the acute phase of COVID-19 respiratory syndrome in neurologically asymptomatic or oligosymptomatic patients. The most frequent finding is marked hypermetabolism in evolutionary ancient structures such as lenticular nucleus and thalami. Neocortical metabolism was reduced in up to one third of patients, suggesting a redistribution of brain metabolism from the neocortex to evolutionary ancient brain structures in these patients.

Background: Glioblastoma is an extremely aggressive malignant tumor with a very poor prognosis. Due to the increased proliferation rate of glioblastoma, there is the development of hypoxic regions, characterized by an increased concentration of copper (Cu). Considering this, ⁶⁴Cu has attracted attention as a possible theranostic radionuclide for glioblastoma. In particular, [⁶⁴Cu]CuCl₂ accumulates in glioblastoma, being considered a suitable agent for positron emission tomography. Here, we explore further the theranostic potential of [⁶⁴Cu]CuCl₂, by studying its therapeutic effects in advanced three-dimensional glioblastoma cellular models. First, we established spheroids from three glioblastoma (T98G, U373, and U87) and a non-tumoral astrocytic cell line. Then, we evaluated the therapeutic responses of spheroids to [⁶⁴Cu]CuCl₂ exposure by analyzing spheroids' growth, viability, and cells' proliferative capacity. Afterward, we studied possible mechanisms responsible for the therapeutic outcomes, including the uptake of ⁶⁴Cu, the expression levels of a copper transporter (CTR1), the presence of a cancer stem cell population, and the production of reactive oxygen species (ROS).

Results: Results revealed that [⁶⁴Cu]CuCl₂ is able to significantly reduce spheroids' growth and viability, while also affecting cells' proliferation capacity. The uptake of ⁶⁴Cu, the presence of cancer stem-like cells and the production of ROS were in accordance with the therapeutic response. However, expression levels of CTR1 were not in agreement with uptake levels, revealing that other mechanisms could be involved in the uptake of ⁶⁴Cu.

Conclusions: Overall, our results further support [⁶⁴Cu]CuCl₂ potential as a theranostic agent for glioblastoma, unveiling potential mechanisms that could be involved in the therapeutic response.

Background: Meta-analysis show the diagnostic performance of cardiac dedicated multi-pinhole cadmium-zinc-telluride myocardial perfusion imaging (MPI) with a sensibility around 0.9 and a specificity around 0.7. The aim of the present study is to explore a simple method to generate less artefact on MPI using single photon emission computed tomography (SPECT) and to enhance specificity without changing sensibility.

Results: From October 2018 to March 2019, 200 patients who underwent SPECT with [^99mTc]Tc-tetrofosmin were prospectively recruited: 100 patients with ischemia or necrosis diagnosis (first arm), and 100 patients with myocardial reversible SPECT artefact (second arm). Each SPECT was explored using two image process based on a Butterworth prefilter and post-filter: the original image processing (reconstruction A) with a cut-off frequency equals to 37% of the Nyquist frequency and order equals to 7, and a second image processing (reconstruction B) with a cut-off frequency equals to 25% of the Nyquist frequency and order equals to 5. For each patient, sum stress or rest score with and without septum (SSRS and SSRSws) were calculated with the two reconstructions. No significant statistical difference between SSRSa and SSRSb was identified for the first arm (P = 0.54) and the relative difference ∆r was - 0.5 ± 11.1% (95% CI - 2.7 to 1.7). We found a significant statistical difference between SSRSa and SSRSb for the second arm (p < 0.0001) and the relative difference ∆r was 69.7 ± 16.2% (95% CI 66.6-72.9).

Conclusion: In conclusion, using a Butterworth prefilter and post-filter cut-off frequency equal to 25% of the Nyquist frequency before iterative reconstruction generates less artefact and improves myocardial SPECT specificity without affecting sensibility compared with the original reconstruction.

Background: P2X7 receptor has emerged as a potentially superior PET imaging marker to TSPO, the gold standard for imaging glial reactivity. [¹¹C]SMW139 is the most recently developed radiotracer to image P2X7 receptor. The aim of this study was to image reactive glia in the APP/PS1-21 transgenic (TG) mouse model of Aβ deposition longitudinally using [¹¹C]SMW139 targeting P2X7 receptor and to compare tracer uptake to that of [¹⁸F]F-DPA targeting TSPO at the final imaging time point. TG and wild type (WT) mice underwent longitudinal in vivo PET imaging using [¹¹C]SMW139 at 5, 8, 11, and 14 months, followed by [¹⁸F]F-DPA PET scan only at 14 months. In vivo imaging results were verified by ex vivo brain autoradiography, immunohistochemical staining, and analysis of [¹¹C]SMW139 unmetabolized fraction in TG and WT mice.

Results: Longitudinal change in [¹¹C]SMW139 standardized uptake values (SUVs) showed no statistically significant increase in the neocortex and hippocampus of TG or WT mice, which was consistent with findings from ex vivo brain autoradiography. Significantly higher [¹⁸F]F-DPA SUVs were observed in brain regions of TG compared to WT mice. Quantified P2X7-positive staining in the cortex and thalamus of TG mice showed a minor increase in receptor expression with ageing, while TSPO-positive staining in the same regions showed a more robust increase in expression in TG mice as they aged. [¹¹C]SMW139 was rapidly metabolized in mice, with 33% of unmetabolized fraction in plasma and 29% in brain homogenates 30 min after injection.

Conclusions: [¹¹C]SMW139, which has a lower affinity for the rodent P2X7 receptor than the human version of the receptor, was unable to image the low expression of P2X7 receptor in the APP/PS1-21 mouse model. Additionally, the rapid metabolism of [¹¹C]SMW139 in mice and the presence of several brain-penetrating radiometabolites significantly impacted the analysis of in vivo PET signal of the tracer. Finally, [¹⁸F]F-DPA targeting TSPO was more suitable for imaging reactive glia and neuroinflammatory processes in the APP/PS1-21 mouse model, based on the findings presented in this study and previous studies with this mouse model.

Background: Correct classification of estrogen receptor (ER) status is essential for prognosis and treatment planning in patients with breast cancer (BC). Therefore, it is recommended to sample tumor tissue from an accessible metastasis. However, ER expression can show intra- and intertumoral heterogeneity. 16α-[¹⁸F]fluoroestradiol ([¹⁸F]FES) Positron Emission Tomography/Computed Tomography (PET/CT) allows noninvasive whole-body (WB) identification of ER distribution and is usually performed as a single static image 60 min after radiotracer injection. Using dynamic whole-body (D-WB) PET imaging, we examine [¹⁸F]FES kinetics and explore whether Patlak parametric images ( $K_i$ ) are quantitative and improve lesion visibility.

Results: This prospective study included eight patients with metastatic ER-positive BC scanned using a D-WB PET acquisition protocol. The kinetics of [¹⁸F]FES were best characterized by the irreversible two-tissue compartment model in tumor lesions and in the majority of organ tissues. $K_i$ values from Patlak parametric images correlated with $K_i$ values from the full kinetic analysis, r² = 0.77, and with the semiquantitative mean standardized uptake value (SUV_mean), r² = 0.91. Furthermore, parametric $K_i$ images had the highest target-to-background ratio (TBR) in 162/164 metastatic lesions and the highest contrast-to-noise ratio (CNR) in 99/164 lesions compared to conventional SUV images. TBR was 2.45 (95% confidence interval (CI): 2.25-2.68) and CNR 1.17 (95% CI: 1.08-1.26) times higher in $K_i$ images compared to SUV images. These quantitative differences were seen as reduced background activity in the $K_i$ images.

Conclusion: [¹⁸F]FES uptake is best described by an irreversible two-tissue compartment model. D-WB [¹⁸F]FES PET/CT scans can be used for direct reconstruction of parametric $K_i$ images, with superior lesion visibility and $K_i$ values comparable to $K_i$ values found from full kinetic analyses. This may aid correct ER classification and treatment decisions. Trial registration ClinicalTrials.gov: NCT04150731, https://clinicaltrials.gov/study/NCT04150731.

Background: We recently introduced radiohybrid (rh)-based minigastrin analogs e.g., DOTA-rhCCK-18 (DOTA-D-Dap(p-SiFA)-(D-γ-Glu)₈-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH₂), that revealed substantially increased activity retention in the tumor. However, one major drawback of these first generation rh-based cholecystokinin-2 receptor (CCK-2R) ligands is their elevated activity levels in the kidneys, especially at later time points (24 h p.i.). Therefore, this study aimed to reduce kidney retention with regard to a therapeutic use via substitution of negatively charged D-glutamic acid moieties by hydrophilic uncharged polyethylene glycol (PEG) linkers of various length ((PEG)₄ to (PEG)₁₁). Furthermore, the influence of differently charged silicon-based fluoride acceptor (SiFA)-moieties (p-SiFA: neutral, SiFA-ipa: negatively charged, and SiFAlin: positively charged) on in vitro properties of minigastrin analogs was evaluated. Out of all compounds evaluated in vitro, the two most promising minigastrin analogs were further investigated in vivo.

Results: CCK-2R affinity of most compounds evaluated was found to be in a range of 8-20 nM (by means of apparent IC₅₀), while ligands containing a SiFA-ipa moiety displayed elevated IC₅₀ values. Lipophilicity was noticeably lower for compounds containing a D-γ-glutamate (D-γ-Glu) moiety next to the D-Dap(SiFA) unit as compared to their counterparts lacking the additional negative charge. Within this study, combining the most favorable CCK-2R affinity and lipophilicity, [^177/natLu]Lu-DOTA-rhCCK-70 (DOTA-D-Dap(p-SiFA)-D-γ-Glu-(PEG)₇-D-γ-Glu-(PEG)₃-Trp-(N-Me)Nle-Asp-1-Nal-NH₂; IC₅₀: 12.6 ± 2.0 nM; logD_7.4: - 1.67 ± 0.08) and [^177/natLu]Lu-DOTA-rhCCK-91 (DOTA-D-Dap(SiFAlin)-D-γ-Glu-(PEG)₄-D-γ-Glu-(PEG)₃-Trp-(N-Me)Nle-Asp-1-Nal-NH₂; IC₅₀: 8.6 ± 0.7 nM; logD_7.4 =  - 1.66 ± 0.07) were further evaluated in vivo. Biodistribution data of both compounds revealed significantly reduced (p < 0.0001) activity accumulation in the kidneys compared to [¹⁷⁷Lu]Lu-DOTA-rhCCK-18 at 24 h p.i., leading to enhanced tumor-to-kidney ratios despite lower tumor uptake. However, overall tumor-to-background ratios of the novel compounds were lower than those of [¹⁷⁷Lu]Lu-DOTA-rhCCK-18.

Conclusion: We could show that the reduction of negative charges within the linker section of radiohybrid-based minigastrin analogs led to decreased activity levels in the kidneys at 24 h p.i., while maintaining a good tumor uptake. Thus, favorable tumor-to-kidney ratios were accomplished in vivo. However, further optimization has to be done in order to improve tumor retention and general biodistribution profile.

Background: Cisplatin- based chemoradiotherapy is a crucial pillar in the treatment of HNSCC. The use of cisplatin comes with high toxicity rates as 35% of patients cannot sustain the planned dose while response is unpredictable. Unfortunately, there are no clinically applicable biomarkers to predict response. Based on the association of response with the number of DNA adducts and the involved molecular pathway to resolve cisplatin-induced DNA crosslinks in HNSCC, [195mPt]cisplatin (CISSPECT®) might have potential to monitor drug uptake and retention before treatment, and predict cisplatin response. The aim of this study is to investigate this concept by analyzing uptake, retention and biodistribution of [195mPt]cisplatin between known cisplatin-sensitive (VU-SCC-1131) and -resistant (VU-SCC-OE) HNSCC cell lines in vitro and xenografted in mice in vivo.

Results: By a variety of experiments in vitro, including cell cycle analyses, and in vivo, the sensitivity of cell line VU-SCC-1131 and resistance of cell line VU-SCC-OE for cisplatin was demonstrated. VU-SCC-OE was able to accumulate more [195mPt]cisplatin in the DNA, and showed an increased capability to repair [195mPt]cisplatin crosslinks compared to VU-SCC-1131. Notably, DNA binding of cisplatin increased even when cisplatin was removed from the medium, likely from intracellular sources. In vivo, [195mPt]cisplatin showed a rapid biodistribution to the large organs such as the liver, with no differences between intravenous and intraperitoneal administration. Most circulating [195mPt]cisplatin was cleared by renal filtration, and accumulation in kidney and liver remained high. Uptake in xenografts was rapid (blood:tumor ratio; 1:1) and highest after 1 h, while decreasing after 6 h in line with the concentration in the blood. Remarkably, there was no significant difference in uptake or retention between xenografts of the cisplatin-sensitive and -resistant cell line.

Conclusion: VU-SCC-1131 with a known FA deficiency and VU-SCC-OE displayed a significant difference in sensitivity to and recovery from cisplatin treatment, due to S-phase problems in VU-SCC-1131 at low doses, in line with the genetic defect. Using Pt-195m radioactivity analysis, we demonstrated the limited capability of cisplatin crosslink repair in VU-SCC-1131. Unexpectedly, we were not able to translate these findings to a mouse model for sensitivity prediction based on the biodistribution in the tumor, most likely as other factors such as influx counterbalanced repair. These data do not support response prediction by [195mPt]cisplatin, and applications to predict the toxic side-effects of cisplatin and to tailor dosing schemes seem more feasible.

Background: ¹⁸F-FDG positron emission tomography (PET) plays a crucial part in the evaluation for pediatric epileptic patients prior to therapy. Short-term scanning holds significant importance, especially for pediatrics epileptic individuals who exhibited involuntary movements. The aim was to evaluate the effects of short acquisition time on image quality and lesion detectability in pediatric epileptic patients using total-body (TB) PET/CT. A total of 25 pediatric patients who underwent TB PET/CT using uEXPLORER scanner with an ¹⁸F-FDG administered dose of 3.7 MBq/kg and an acquisition time of 600 s were retrospectively enrolled. Short acquisition times (60 s, 150 and 300 s) were simulated by truncating PET data in list mode to reduce count density. Subjective image quality was scored on a 5-point scale. Regions of interest analysis of suspected epileptogenic zones (EZs), corresponding locations contralateral to EZs, and healthy cerebellar cortex were used to compare the semi-quantitative uptake indices of short-time images and then were compared with 600 s images. The comparison of EZs detectability based on time-dependent PET images was performed.

Results: Our study demonstrated that a short acquisition time of 150 s is sufficient to maintain subjective image quality and lesion significance. Statistical analysis revealed no significant difference in subjective PET image quality between imaging at 300 s and 150 s (P > 0.05). The overall impression scores of image quality and lesion conspicuity in G60s were both greater than 3 (overall quality, 3.21 ± 0.46; lesion conspicuity, 4.08 ± 0.74). As acquisition time decreased, the changes of SUVmax and SD in the cerebellar cortex gradually increased (P < 0.01). There was no significant difference in asymmetry index (AI) difference between the groups and the AIs of EZs were > 15% in all groups. In 26 EZs of 25 patients, the lesion detection rate was still 100% when the time was reduced to 60 s.

Conclusions: This study proposed that TB PET/CT acquisition time could be reduced to 60 s with acceptable lesion detectability. Furthermore, it was suggested that a 150 s acquisition time would be sufficient to achieve diagnostic performance and image quality for children with epilepsy.