Journal of Nuclear Medicine最新文献

Huntington disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine (CAG) trinucleotide expansion in the huntingtin (HTT) gene that encodes the mutant huntingtin protein (mHTT). Visualization and quantification of cerebral mHTT will provide a proxy for target engagement and a means to evaluate therapeutic interventions aimed at lowering mHTT in the brain. Here, we validated the novel radioligand ¹¹C-labeled 6-(5-((5-methoxypyridin-2-yl)methoxy)benzo[d]oxazol-2-yl)-2-methylpyridazin-3(2H)-one (¹¹C-CHDI-180R) using PET imaging to quantify cerebral mHTT aggregates in a macaque model of HD. Methods: Rhesus macaques received MRI-guided intrastriatal delivery of a mixture of AAV2 and AAV2.retro viral vectors expressing an HTT fragment bearing 85 CAG repeats (85Q, n = 5), a control HTT fragment bearing 10 CAG repeats (10Q, n = 4), or vector diluent only (phosphate-buffered saline, n = 5). Thirty months after surgery, 90-min dynamic PET/CT imaging was used to investigate ¹¹C-CHDI-180R brain kinetics, along with serial blood sampling to measure input function and stability of the radioligand. The total volume of distribution was calculated using a 2-tissue-compartment model as well as Logan graphical analysis for regional quantification. Immunostaining for mHTT was performed to corroborate the in vivo findings. Results: ¹¹C-CHDI-180R displayed good metabolic stability (51.4% ± 4.0% parent in plasma at 60 min after injection). Regional time-activity curves displayed rapid uptake and reversible binding, which were described by a 2-tissue-compartment model. Logan graphical analysis was associated with the 2-tissue-compartment model (r ² = 0.96, P < 0.0001) and used to generate parametric volume of distribution maps. Compared with controls, animals administered the 85Q fragment exhibited significantly increased ¹¹C-CHDI-180R binding in several cortical and subcortical brain regions (group effect, P < 0.0001). No difference in ¹¹C-CHDI-180R binding was observed between buffer and 10Q animals. The presence of mHTT aggregates in the 85Q animals was confirmed histologically. Conclusion: We validated ¹¹C-CHDI-180R as a radioligand to visualize and quantify mHTT aggregated species in a HD macaque model. These findings corroborate our previous work in rodent HD models and show that ¹¹C-CHDI-180R is a promising tool to assess the mHTT aggregate load and the efficacy of therapeutic strategies.

Shortwave infrared (900-1,700 nm) fluorescence imaging (SWIRFI) has shown significant advantages over visible (400-650 nm) and near-infrared (700-900 nm) fluorescence imaging (reduced autofluorescence, improved contrast, tissue resolution, and depth sensitivity). However, there is a major lag in the clinical translation of preclinical SWIRFI systems and targeted SWIRFI probes. Methods: We preclinically show that the pH low-insertion peptide conjugated to indocyanine green (pHLIP ICG), currently in clinical trials, is an excellent candidate for cancer-targeted SWIRFI. Results: pHLIP ICG SWIRFI achieved picomolar sensitivity (0.4 nM) with binary and unambiguous tumor screening and resection up to 96 h after injection in an orthotopic breast cancer mouse model. SWIRFI tumor screening and resection had ambient light resistance (possible without gating or filtering) with outstanding signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) values at exposures from 10 to 0.1 ms. These SNR and CNR values were also found for the extended emission of pHLIP ICG in vivo (>1,100 nm, 300 ms). Conclusion: SWIRFI sensitivity and ambient light resistance enabled continued tracer clearance tracking with unparalleled SNR and CNR values at video rates for tumor delineation (achieving a tumor-to-muscle ratio above 20). In total, we provide a direct precedent for the democratic translation of an ambient light resistant SWIRFI and pHLIP ICG ecosystem, which can instantly improve tumor resection.

The human epidermal growth factor receptor 2 (HER2)-targeting trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are antibody-drug conjugates (ADC) clinically used to treat HER2-positive breast cancer, with the latter receiving clinical approval in 2021 for HER2-positive gastric cancer. Lovastatin, a cholesterol-lowering drug, temporally elevates cell-surface HER2 in ways that enhance HER2-ADC binding and internalization. Methods: In an NCIN87 gastric xenograft model and a gastric patient-derived xenograft model, we used the ⁸⁹Zr-labeled or ⁶⁴Cu-labeled anti-HER2 antibody trastuzumab to investigate the dosing regimen of ADC therapy with and without coadministration of lovastatin. We compared the ADC efficacy of a multiple-dose ADC regime, which replicates the clinical dose regimen standard, with a single-dose regime. Results: T-DM1/lovastatin treatment inhibited tumor growth, regardless of multiple- or single-dose T-DM1 administration. Coadministration of lovastatin with T-DM1 or T-DXd as a single dose enhanced tumor growth inhibition, which was accompanied by a decrease in signal on HER2-targeted immuno-PET and a decrease in HER2-mediated signaling at the cellular level. DNA damage signaling was increased on ADC treatment in vitro. Conclusion: Our data from a gastric cancer xenograft show the utility of HER2-targeted immuno-PET to inform the tumor response to ADC therapies in combination with modulators of cell-surface target availability. Our studies also demonstrate that statins enhance ADC efficacy in both a cell-line and a patient-derived xenograft model in ways that enable a single-dose administration of the ADC.

Fibroblast activation protein contributes to immunosuppression and resistance to immunotherapies. This study aimed to compare baseline ⁶⁸Ga-labeled fibroblast activation protein inhibitor (⁶⁸Ga-FAPI) PET/CT and ¹⁸F-FDG PET/CT in response and survival prediction in unresectable hepatocellular carcinoma (uHCC) patients treated with the combination of programmed cell death 1 (PD-1) inhibitor and lenvatinib. Methods: In this prospective cohort study, 22 patients with uHCC who underwent baseline ¹⁸F-FDG and ⁶⁸Ga-FAPI PET/CT and soon began taking a combination of PD-1 inhibitor and lenvatinib were recruited. Semiquantitative indices of baseline PET/CT were measured as ¹⁸F-FDG SUV_max, metabolic tumor volume, total lesion glycolysis, ⁶⁸Ga-FAPI SUV_max, ⁶⁸Ga-FAPI-avid tumor volume (FTV), and total lesion fibroblast activation protein expression (TLF). The primary endpoint was durable or nondurable clinical benefit after treatment, and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: The overall response rate of the combination therapy was 41% (9/22). Fifty percent of patients had durable clinical benefit. Median PFS and OS were 4.8 and 14.4 mo, respectively. Patients with nondurable clinical benefit showed a significantly higher FTV and TLF than those with durable clinical benefit, whereas ¹⁸F-FDG parameters overlapped. A higher ⁶⁸Ga-FAPI-avid tumor burden (FTV > 230.46 cm³ or TLF > 961.74 SUV_{body weight}⋅cm³) predicted both shorter PFS (4.0 vs. 13.5 mo, P = 0.016) and shorter OS (7.8 mo vs. not reached, P = 0.030). Patients with a higher metabolic tumor burden (metabolic tumor volume > 206.80 cm³ or total lesion glycolysis > 693.53 SUV_{body weight}⋅cm³) showed a shorter OS although the difference did not reach statistical significance (P = 0.085). In multivariate analysis, a higher ⁶⁸Ga-FAPI-avid tumor burden (hazard ratio [HR], 3.88 [95% CI, 1.26-12.01]; P = 0.020) and macrovascular invasion (HR, 4.00 [95% CI, 1.06-15.14]; P = 0.039) independently predicted a shorter PFS, whereas a higher ⁶⁸Ga-FAPI-avid tumor burden (HR, 5.92 [95% CI, 1.19-29.42]; P = 0.035) and bone metastases (HR, 5.88 [95% CI, 1.33-25.93]; P = 0.022) independently predicted a shorter OS. Conclusion: Volumetric indices on baseline ⁶⁸Ga-FAPI PET/CT were potentially independent prognostic factors to predict durable clinical benefit, PFS, and OS in uHCC patients treated with a combination of PD-1 and lenvatinib. Baseline ⁶⁸Ga-FAPI PET/CT may facilitate uHCC patient selection before combination therapy.

Early use of targeted radionuclide therapy to eradicate tumor cell clusters and micrometastases might offer cure. However, there is a need to select appropriate radionuclides and assess the potential impact of heterogeneous targeting. Methods: The Monte Carlo code CELLDOSE was used to assess membrane and nuclear absorbed doses from ¹⁷⁷Lu and ¹⁶¹Tb (β^--emitter with additional conversion and Auger electrons) in a cluster of 19 cells (14-μm diameter, 10-μm nucleus). The radionuclide distributions considered were cell surface, intracytoplasmic, or intranuclear, with 1,436 MeV released per labeled cell. To model heterogeneous targeting, 4 of the 19 cells were unlabeled, their position being stochastically determined. We simulated situations of single targeting, as well as dual targeting, with the 2 radiopharmaceuticals aiming at different targets. Results: ¹⁶¹Tb delivered 2- to 6-fold higher absorbed doses to cell membranes and 2- to 3-fold higher nuclear doses than ¹⁷⁷Lu. When all 19 cells were targeted, membrane and nuclear absorbed doses were dependent mainly on radionuclide location. With cell surface location, membrane absorbed doses were substantially higher than nuclear absorbed doses, both with ¹⁷⁷Lu (38-41 vs. 4.7-7.2 Gy) and with ¹⁶¹Tb (237-244 vs. 9.8-15.1 Gy). However, when 4 cells were not targeted by the cell surface radiopharmaceutical, the membranes of these cells received on average only 9.6% of the ¹⁷⁷Lu absorbed dose and 2.9% of the ¹⁶¹Tb dose, compared with a cluster with uniform cell targeting, whereas the impact on nuclear absorbed doses was moderate. With an intranuclear radionuclide location, the nuclei of unlabeled cells received only 17% of the ¹⁷⁷Lu absorbed dose and 10.8% of the ¹⁶¹Tb dose, compared with situations with uniform targeting. With an intracytoplasmic location, nuclear and membrane absorbed doses to unlabeled cells were one half to one quarter those obtained with uniform targeting, both for ¹⁷⁷Lu and for ¹⁶¹Tb. Dual targeting was beneficial in minimizing absorbed dose heterogeneities. Conclusion: To eradicate tumor cell clusters, ¹⁶¹Tb may be a better candidate than ¹⁷⁷Lu. Heterogeneous cell targeting can lead to substantial heterogeneities in absorbed doses. Dual targeting was helpful in reducing dose heterogeneity and should be explored in preclinical and clinical studies.

Patients with metastatic prostate cancer are more likely than other groups to present for radiopharmaceutical therapy with urinary incontinence due to complications from prior local prostate cancer treatment. A consequence of urinary incontinence in patients receiving radiopharmaceutical therapy is the potential production of contaminated solid waste, which must be managed by the licensee and, at home, managed by and disposed of by the patient. Prolonging the patient stay in the treating facility after radiopharmaceutical therapy administration, until the first urinary void or potentially overnight, may moderately reduce the quantity of contaminated waste being managed by the patient at home. However, this approach does not fully mitigate the need for a patient waste-management strategy. In this brief communication, the relative radiation safety merits of contaminated waste disposal in the normal household waste stream in comparison to other waste management strategies are evaluated.

The favorable decay characteristics of ¹⁶¹Tb attracted the interest of clinicians in using this novel radionuclide for radioligand therapy (RLT). ¹⁶¹Tb decays with a similar half-life to ¹⁷⁷Lu, but beyond the emission of β^--particles and γ-rays, ¹⁶¹Tb also emits conversion and Auger electrons, which may be particularly effective to eliminate micrometastases. The aim of this study was to compare the dosimetry and therapeutic efficacy of ¹⁶¹Tb and ¹⁷⁷Lu in tumor-bearing mice using SibuDAB and PSMA-I&T, which differ in their blood residence time and tumor uptake. Methods: [¹⁶¹Tb]Tb-SibuDAB and [¹⁶¹Tb]Tb-PSMA-I&T were evaluated in vitro and investigated in biodistribution, imaging, and therapy studies using PC-3 PIP tumor-bearing mice. The ¹⁷⁷Lu-labeled counterparts served for dose calculations and comparison of therapeutic efficacy. The tolerability of RLT in mice was monitored on the basis of body mass, blood plasma parameters, blood cell counts, and the histology of relevant organs and tissues. Results: The prostate-specific membrane antigen (PSMA)-targeting radioligands, irrespective of whether labeled with ¹⁶¹Tb or ¹⁷⁷Lu, showed similar in vitro data and comparable tissue distribution profiles. As a result of the albumin-binding properties, [¹⁶¹Tb]Tb/[¹⁷⁷Lu]Lu-SibuDAB had an enhanced blood residence time and higher tumor uptake (62%-69% injected activity per gram at 24 h after injection) than [¹⁶¹Tb]Tb/[¹⁷⁷Lu]Lu-PSMA-I&T (30%-35% injected activity per gram at 24 h after injection). [¹⁶¹Tb]Tb-SibuDAB inhibited tumor growth more effectively than [¹⁶¹Tb]Tb-PSMA-I&T, as can be ascribed to its 4-fold increased absorbed tumor dose. At any of the applied activities, the ¹⁶¹Tb-based radioligands were therapeutically more effective than their ¹⁷⁷Lu-labeled counterparts, as agreed with the approximately 40% increased tumor dose of ¹⁶¹Tb compared with that of ¹⁷⁷Lu. Under the given experimental conditions, no obvious adverse events were observed. Conclusion: The data of this study indicate the promising potential of ¹⁶¹Tb in combination with SibuDAB for RLT of prostate cancer. Future clinical studies using ¹⁶¹Tb-based RLT will shed light on a potential clinical benefit of ¹⁶¹Tb over ¹⁷⁷Lu.