The Journal of Nuclear Medicine最新文献

{"title":"Localized In Vivo Prodrug Activation Using Radionuclides","authors":"Jeremy M. Quintana, Fangchao Jiang, Mikyung Kang, Victor Valladolid Onecha, Arda Könik, Lei Qin, Victoria E. Rodriguez, Huiyu Hu, Nicholas Borges, Ishaan Khurana, Leou I. Banla, Mariane Le Fur, Peter Caravan, Jan Schuemann, Alejandro Bertolet, Ralph Weissleder, Miles A. Miller, Thomas S.C. Ng","doi":"10.2967/jnumed.124.268559","DOIUrl":"https://doi.org/10.2967/jnumed.124.268559","url":null,"abstract":"<p>Radionuclides used for imaging and therapy can show high molecular specificity in the body with appropriate targeting ligands. We hypothesized that local energy delivered by molecularly targeted radionuclides could chemically activate prodrugs at disease sites while avoiding activation in off-target sites of toxicity. As proof of principle, we tested whether this strategy of radionuclide-induced drug engagement for release (RAiDER) could locally deliver combined radiation and chemotherapy to maximize tumor cytotoxicity while minimizing off-target exposure to activated chemotherapy. <b>Methods:</b> We screened the ability of radionuclides to chemically activate a model radiation-activated prodrug consisting of the microtubule-destabilizing monomethyl auristatin E (MMAE) caged by a radiation-responsive phenyl azide, and we interpreted experimental results using the radiobiology computational simulation suite TOPAS-nBio. RAiDER was evaluated in syngeneic mouse models of cancer using the fibroblast activation protein inhibitor (FAPI) agents [^99mTc]Tc-FAPI-34 and [¹⁷⁷Lu]Lu-FAPI-04 and the prostate-specific membrane antigen (PSMA) agent [¹⁷⁷Lu]Lu-PSMA-617, combined with caged MMAE or caged exatecan. Biodistribution in mice, combined with clinical dosimetry, estimated the relationship between radiopharmaceutical uptake in patients and anticipated concentrations of activated prodrug using RAiDER. <b>Results:</b> RAiDER efficiency varied by 70-fold across radionuclides (^99mTc &gt; ¹¹¹In &gt; ¹⁷⁷Lu &gt; ⁶⁴Cu &gt; ³²P &gt; ⁶⁸Ga &gt; ²²³Ra &gt; ¹⁸F), yielding up to 320 nM prodrug activation/Gy of exposure from ^99mTc. Computational simulations implicated low-energy electron&ndash;mediated free radical formation as driving prodrug activation. Radionuclide-activated caged MMAE restored the prodrug&rsquo;s ability to destabilize microtubules and increased its cytotoxicity by up to 2,600-fold that of the nonactivated prodrug. Mice treated with [^99mTc]Tc-FAPI-34 and caged MMAE accumulated concentrations of activated MMAE that were up to 3,000 times greater in tumors than in other tissues. RAiDER with [^99mTc]Tc-FAPI-34 or [¹⁷⁷Lu]Lu-FAPI-04 delayed tumor growth, whereas monotherapies did not (<I>P</I> &lt; 0.003). Clinically guided dosimetry suggests sufficient radiation doses can be delivered to activate therapeutically meaningful levels of prodrug. <b>Conclusion:</b> This proof-of-concept study shows that RAiDER is compatible with multiple radionuclides commonly used in nuclear medicine and can potentially improve the efficacy of radiopharmaceutical therapies to treat cancer safely. RAiDER thus shows promise as an effective strategy to treat disseminated malignancies and broadens the capability of radiopharmaceuticals to trigger diverse biologic and therapeutic responses.</p>","PeriodicalId":22820,"journal":{"name":"The Journal of Nuclear Medicine","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mathematic Modeling of Tumor Growth During [177Lu]Lu-PSMA Therapy: Insights into Treatment Optimization","authors":"Nouran R.R. Zaid, Remco Bastiaannet, Rob Hobbs, George Sgouros","doi":"10.2967/jnumed.124.268457","DOIUrl":"https://doi.org/10.2967/jnumed.124.268457","url":null,"abstract":"<p>The treatment regimen for [¹⁷⁷Lu]Lu-prostate-specific membrane antigen (PSMA) 617 therapy follows that of chemotherapy: 6 administrations of a fixed activity, each separated by 6 wk. Mathematic modeling can be used to test the hypothesis that the current treatment regimen for a radiopharmaceutical modality is suboptimal. <strong>Methods:</strong> A mathematic model was developed to describe tumor growth during [¹⁷⁷Lu]Lu-PSMA therapy. The model examined alternative treatment schedules to maximize tumor mass reduction while still maintaining an acceptable biologically effective dose to kidneys. Median patients’ pharmacokinetics from literature reports were used to obtain the dose rate over time. The model incorporates the Gompertz tumor growth and linear quadratic models to describe the effect of radiation-induced cell kill on tumor growth. For a fixed total activity of 44.4 GBq of [¹⁷⁷Lu]Lu-PSMA-617 and a 6-wk interval between cycles, the efficacy of the standard fractionation (6-cycle) treatment schedule was compared with different treatment regimens for a distribution of published tumor masses. A treatment schedule whereby 7.4 GBq are administered in the first cycle, and the remaining activity (37 GBq) in the second cycle (1-2-cycle treatment), was examined. <strong>Results:</strong> When tumor mass nadir was used as the optimization metric, a lower tumor burden (e.g., &lt;4 g) was insensitive to the number of cycles; the 6-cycle treatment was equivalent to the 1-2-cycle treatment. For larger masses, fewer cycles yielded better results. For a 7-g tumor, the 5-cycle, 4-cycle, 3-cycle and 1-2-cycle schedules were 24%, 50%, 76%, and 84% more efficacious, respectively, than the 6-cycle schedule. The absorbed doses to kidneys, parotid glands, lacrimal glands, and red marrow were 23, 16, 70, and 1 Gy, respectively. In all fractionated schedules, the biologically effective dose to kidneys was within tolerance (&lt;40 Gy). <strong>Conclusion:</strong> On the basis of model-derived simulations, treatment delivered in a 1-2-cycle schedule is recommended to achieve better outcomes for patients undergoing [¹⁷⁷Lu]Lu-PSMA therapy.</p>","PeriodicalId":22820,"journal":{"name":"The Journal of Nuclear Medicine","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Fibroblast Activation Protein for Molecular Imaging of Fibrotic Remodeling in Pulmonary Arterial Hypertension","authors":"Peng Hou, Haiming Chen, Sihao Liang, Wenliang Guo, Ruiyue Zhao, Huailu Pan, Haimin Liu, Youcai Li, Jie Lv, Kaixiang Zhong, Miao Ke, Yimin Fu, Huizhen Zhong, Xinlu Wang, Cheng Hong","doi":"10.2967/jnumed.124.268376","DOIUrl":"https://doi.org/10.2967/jnumed.124.268376","url":null,"abstract":"<p>The purpose of this study was to investigate the feasibility of using ¹⁸F-labeled fibroblast activation protein inhibitor (FAPI) PET/CT in assessing the fibrotic remodeling of the pulmonary artery (PA) and the right ventricle (RV) in pulmonary arterial hypertension (PAH). <strong>Methods:</strong> In a rat model of monocrotaline-induced PAH, rats were euthanized at different time points for tissue analysis (fibroblast activation protein immunofluorescence and Masson’s trichrome staining) after completing ¹⁸F-FAPI PET/CT and hemodynamic measurements. Thirty-eight PAH patients were enrolled to participate in ¹⁸F-FAPI PET/CT imaging, with right heart catheterization and echocardiography performed within 1 wk to assess pulmonary hemodynamics and cardiac function. <strong>Results:</strong> In the animal experiments, RV systolic pressure in monocrotaline rats increased from day 14 to day 21 after injection. ¹⁸F-FAPI uptake and fibroblast activation protein expression in the myocardium and lungs peaked on day 14 after injection. Collagen deposition in the RVs and peripheral PAs of monocrotaline rats progressively deteriorated from day 14 to day 21. In the human PAH study, ¹⁸F-FAPI PET/CT imaging identified varying degrees of ¹⁸F-FAPI uptake in the myocardium and proximal and distal PAs, correlating with clinical, RV function, and pulmonary hemodynamic parameters. Among the 5 follow-up patients who underwent a second ¹⁸F-FAPI PET/CT scan after 6 mo (range, 4–9 mo) of PAH-targeted therapy, 3 demonstrated reduced ¹⁸F-FAPI uptake, corresponding with clinical improvement. <strong>Conclusion:</strong> ¹⁸F-FAPI PET/CT imaging is feasible for visualizing the remodeling of the PA and the RV in PAH. Although it offers promise for assessing disease-related changes, its role in evaluating disease severity and monitoring therapeutic efficacy requires further investigation.</p>","PeriodicalId":22820,"journal":{"name":"The Journal of Nuclear Medicine","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924984","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low- and High-Volume Disease in Metastatic Hormone-Sensitive Prostate Cancer: From CHAARTED to PSMA PET—An International Multicenter Retrospective Study","authors":"Lena M. Unterrainer, Thomas A. Hope, Wolfgang P. Fendler, Tristan Grogan, Honest Ndlovu, Wesley Armstrong, Francesco Barbato, Matthias R. Benz, Matthew B. Rettig, Amar U. Kishan, Mike Sathekge, Ken Herrmann, Johannes Czernin, Jeremie Calais","doi":"10.2967/jnumed.124.268441","DOIUrl":"https://doi.org/10.2967/jnumed.124.268441","url":null,"abstract":"<p>High-volume disease (HVD) and low-volume disease (LVD) definitions in metastatic hormone-sensitive prostate cancer (mHSPC) patients are based on conventional imaging (CI) (CT/MRI with bone scan [BS]) according to CHAARTED criteria. HVD and LVD definitions are associated with overall survival and are used for treatment decisions. It remains unknown how these definitions transfer to prostate-specific membrane antigen (PSMA) PET imaging. The aim of this retrospective multicenter study was to compare the CI-based disease volume criteria to PSMA PET–based volume definitions in a CHAARTED-like cohort. <strong>Methods:</strong> mHSPC patients from 5 international sites who underwent PSMA PET/CT or PSMA PET/MRI and BS within a time interval of 100 d and without initiation of a new therapy between the 2 scans were retrospectively included in the analysis. CHAARTED HVD and LVD criteria were applied to BS, CT, MRI, and PSMA PET. HVD was defined by the presence of visceral metastases or at least 4 bone metastases (with ≥1 beyond the spine or pelvis). Whole-body (WB) tumor burden was estimated with the automated bone scan index (aBSI, EXINI v2.0) on BS and with the WB PSMA PET–positive tumor volume (PSMA-TV) on PSMA PET, respectively. <strong>Results:</strong> Sixty-seven patients with paired PSMA PET and BS were included. The median prostate-specific antigen level was 54.9 ng/mL (interquartile range [IQR], 10.4–191.0 ng/mL). On the basis of CI, it was determined that 17 of 67 patients had HVD-CI (25.4%) and 50 of 67 patients had LVD-CI (74.6%). On the basis of PSMA PET, it was determined that 27 of 67 patients had HVD-PET (40.3%) and 24 of 67 patients had LVD-PET (35.8%). In total, 16 of 67 patients (22.4%) had no visible lesion or only locoregional pelvic disease (M0) with PSMA PET (M0-PET). Stage migration between CI and PSMA PET occurred in 27 of 67 patients (40.3%) by both upstaging and downstaging: 11 of 50 (22%) LVD-CI patients were HVD-PET, whereas 1 of 17 (5.9%) HVD-CI and 15 of 50 (30%) of LVD-CI patients were M0-PET. The median WB PSMA-TV and automated BS index were 248.0 mL (IQR, 54.6–1,427.0 mL) and 3.4% (IQR, 1,0–7.2%) for HVD-CI, 25.1 mL (IQR, 6.6–74.6 mL) and 0.1% (IQR, 0.0–0.2%) for LVD-CI, 141.0 mL (IQR, 47.5–458.0 mL) and 0.9% (IQR, 0.04–4.1%) for HVD-PET, and 31.5 mL (IQR, 10.1–67.9 mL) and 0% (IQR, 0–0.1%) for LVD-PET, respectively. The optimal WB PSMA-TV to stratify CI-based CHAARTED LVD-CI versus HVD-CI was 107 mL with a misclassification of 21.9%. <strong>Conclusion:</strong> Compared with CI, addition of PSMA PET leads to M0 downstaging in every third and LVD to HVD upstaging in every fifth mHSPC patient. Future HVD and LVD definitions based on PSMA PET/CT should be adjusted based on patient outcome.</p>","PeriodicalId":22820,"journal":{"name":"The Journal of Nuclear Medicine","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924990","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuclear Cardiology Surrogate Biomarkers in Clinical Trials","authors":"Robert J.H. Miller, Krishna K. Patel, Jacek Kwiecinski, Leandro Slipczuk, Marc Dweck, David E. Newby, Panithaya Chareonthaitawee, Piotr Slomka","doi":"10.2967/jnumed.124.267869","DOIUrl":"https://doi.org/10.2967/jnumed.124.267869","url":null,"abstract":"<p>Nuclear cardiology offers a diverse range of imaging tools that provide valuable insights into myocardial perfusion, inflammation, metabolism, neuroregulation, thrombosis, and microcalcification. These techniques are crucial not only for diagnosing and managing cardiovascular conditions but also for gaining pathophysiologic insights. Surrogate biomarkers in nuclear cardiology, represented by detectable imaging changes, correlate with disease processes or therapeutic responses and can serve as endpoints in clinical trials when they demonstrate a clear link with these processes. By providing early indicators of therapeutic efficacy—often before clinical outcomes manifest—surrogate biomarkers can accelerate treatment development. This disease-focused review will highlight key nuclear cardiology surrogate biomarkers, emphasizing the importance of standardized imaging protocols and robust quantitative techniques to ensure accuracy and reproducibility. We will also explore the challenges to the broader adoption of imaging biomarkers, including the need for well-defined pathophysiologic correlations, greater data diversity in clinical research, and overcoming regulatory barriers. Addressing these challenges will improve the utility of imaging biomarkers in clinical trials, enabling more precise cardiovascular care through early diagnosis and therapeutic monitoring, ultimately accelerating the development of novel cardiovascular therapies.</p>","PeriodicalId":22820,"journal":{"name":"The Journal of Nuclear Medicine","volume":"75 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924991","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rates of PSMA PET Staging and Positivity in Newly Diagnosed Prostate Cancer in a National Health Care System","authors":"Sean R. Miller, Rachel Tucker Gonzalez, William C. Jackson, Megan E.V. Caram, Phoebe A. Tsao, Kristian Stensland, Yashesh Shah, Daniel Wale, Ka Kit Wong, Benjamin L. Viglianti, David Elliott, Tanner Caverly, Timothy P. Hofer, Sameer Saini, Michael D. Green, Matthew Schipper, Robert T. Dess, Alex K. Bryant","doi":"10.2967/jnumed.124.268555","DOIUrl":"https://doi.org/10.2967/jnumed.124.268555","url":null,"abstract":"<p>Prostate-specific membrane antigen (PSMA) PET was approved by the U.S. Food and Drug Administration in 2020 for the staging of newly diagnosed prostate cancer, yet rates of adoption and real-world positivity rates are unknown. We characterized patients undergoing PSMA PET staging and describe positive findings in a large national cohort. <strong>Methods:</strong> We identified all newly diagnosed prostate cancer patients in the national Veterans Health Administration from June 2020 to August 2023. Demographics, staging imaging reports, and cancer-related information were obtained from electronic medical record data. To assess positive findings, we chart-reviewed 1,994 patients (<em>n</em> = 657 low to intermediate risk) with staging PSMA PET reports available. <strong>Results:</strong> Among 31,838 patients with newly diagnosed prostate cancer, 4,538 (14%) underwent PSMA staging. Use of PSMA staging increased rapidly from near 0 in early 2021 to approximately 70% of patients with high- or very-high-risk disease by August 2023. Among patients who were N0/M0 by conventional imaging, PSMA PET positivity rates (N1 or M1) were 5.9% for favorable intermediate risk, 8.2% for unfavorable intermediate risk, 14% for high risk, and 34% for very high risk. <strong>Conclusion:</strong> PSMA PET staging for newly diagnosed prostate cancer increased rapidly in the Veterans Health Administration. Positivity rates were less than 10% in this large intermediate-risk cohort. These data confirm the utility of PSMA PET staging in high-risk disease and suggest that additional study is needed to refine patient selection in intermediate-risk disease.</p>","PeriodicalId":22820,"journal":{"name":"The Journal of Nuclear Medicine","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2024 SNMMI Highlights Lecture: General Clinical Specialties","authors":"Twyla Bartel","doi":"10.2967/jnumed.124.269263","DOIUrl":"https://doi.org/10.2967/jnumed.124.269263","url":null,"abstract":"<p><em>The Highlights Lecture, presented at the closing session of each SNMMI Annual Meeting, was originated and presented for more than 30 y by Henry N. Wagner, Jr., MD. Beginning in 2010, the duties of summarizing selected significant presentations at the meeting were divided annually among 4 distinguished nuclear and molecular medicine subject matter experts. The 2024 Highlights Lectures were delivered on June 11 at the SNMMI Annual Meeting in Toronto, Canada. Presented here is the lecture by Twyla Bartel, DO, MBA, from Global Advanced Imaging, PLLC (Little Rock, AR), who reviewed general clinical specialties topics from the meeting. Note that in the following presentation summary, numerals in brackets represent abstract numbers as published in</em> The Journal of Nuclear Medicine <em>(2024;65[suppl 2]).</em></p>","PeriodicalId":22820,"journal":{"name":"The Journal of Nuclear Medicine","volume":"96 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Imaging of Cancer Stem Cells and Their Role in Therapy Resistance","authors":"Sofia N. dos Santos, Timothy H. Witney","doi":"10.2967/jnumed.124.267657","DOIUrl":"https://doi.org/10.2967/jnumed.124.267657","url":null,"abstract":"<p>Despite recent therapeutic breakthroughs, cancer patients continue to face high recurrence and mortality rates due to treatment resistance. Cancer stem cells (CSCs), a subpopulation with self-renewal capabilities, are key drivers of refractive disease. This review explores the application of molecular imaging techniques, such as PET and SPECT, for the noninvasive detection of CSCs. By providing real-time monitoring of CSCs, these imaging methods have the potential to predict therapy resistance and guide personalized treatment approaches. Here, we cover the biological characteristics of CSCs, mechanisms of therapy resistance, and the identification and targeting of CSC-specific biomarkers with molecular imaging. Additionally, we address the challenges and opportunities for the clinical translation of CSC imaging, highlighting strategies where CSC imaging can be used to improve patient outcomes.</p>","PeriodicalId":22820,"journal":{"name":"The Journal of Nuclear Medicine","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142924989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical Evaluation and Pilot Clinical Study of CD137 PET Radiotracer for Noninvasive Monitoring Early Responses of Immunotherapy","authors":"Kai Cheng, Luna Ge, Miaomiao Song, Wanhu Li, Jinsong Zheng, Jingru Liu, Yuxi Luo, Pengfei Sun, Shengnan Xu, Zhen Cheng, Jinming Yu, Jie Liu","doi":"10.2967/jnumed.124.268068","DOIUrl":"https://doi.org/10.2967/jnumed.124.268068","url":null,"abstract":"<p>Given the variability in the effectiveness of immune checkpoint blocking therapy among patients and tumor types, development of noninvasive methods for longitudinal assessment of immune cell function and early tumor response is crucial for precision immunotherapy. CD137 (4-1BB), a marker of activated T cells, plays a significant role in immunotherapy. However, its potential as an imaging biomarker for activated T cells in the tumor microenvironment has not been explored. This study introduces a bicyclic peptide–based probe that targets CD137 for noninvasive PET imaging of tumor-infiltrating activated T cells. <strong>Methods:</strong> A bicyclic peptide–based probe, [¹⁸F]AlF-NOTA-BCP137, was first designed and synthesized for quantitative and longitudinal whole-body visualization of CD137 dynamics. Initially, [¹⁸F]AlF-NOTA-BCP137 was assessed in mouse models with varying CD137 expression levels. Next, [¹⁸F]AlF-NOTA-BCP137 was used for longitudinal monitoring of systemic CD137 changes in a humanized tumor-bearing mouse model. Lastly, the probe was further evaluated in a small group of patients with hepatocellular carcinoma undergoing immunotherapy or combination immunotherapy. <strong>Results:</strong> [¹⁸F]AlF-NOTA-BCP137 PET accurately characterized CD137 expression in homologous transplanted mouse models and tumor patients. The findings from animal studies indicated that uptake of [¹⁸F]AlF-NOTA-BCP137 was predictive of the early therapeutic response to combination immunotherapies and was positively associated with the increased survival rates of mice with tumors. A preliminary clinical study involving small patient cohorts demonstrated that [¹⁸F]AlF-NOTA-BCP137 imaging effectively predicted early patient responses to immunotherapeutic interventions. <strong>Conclusion:</strong> [¹⁸F]AlF-NOTA-BCP137 PET imaging of CD137 is a promising and reliable method for evaluating the efficacy of multiple combination immunotherapies and merits further validation in larger-scale clinical trials. This approach has the potential for early noninvasive visualization of individual patient responses in combination cancer immunotherapy and will aid in tailoring personalized strategies for patients.</p>","PeriodicalId":22820,"journal":{"name":"The Journal of Nuclear Medicine","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Acute Hypoxia Exposure on the Availability of A1 Adenosine Receptors and Perfusion in the Human Brain","authors":"Manuel Michno, Jan Schmitz, Anna L. Foerges, Simone Beer, Jens Jordan, Bernd Neumaier, Alexander Drzezga, Daniel Aeschbach, Andreas Bauer, Jens Tank, Henning Weis, Eva-Maria Elmenhorst, David Elmenhorst","doi":"10.2967/jnumed.124.268455","DOIUrl":"https://doi.org/10.2967/jnumed.124.268455","url":null,"abstract":"<p>In animal studies it has been observed that the inhibitory neuromodulator adenosine is released into the cerebral interstitial space during hypoxic challenges. Adenosine’s actions on the A₁ adenosine receptor (A₁AR) protect the brain from oxygen deprivation and overexertion through adjustments in cerebral blood flow, metabolism, and electric activity. <strong>Methods:</strong> Using 8-cyclopentyl-3-(3-[¹⁸F]fluoropropyl)-1-propylxanthine ([¹⁸F]CPFPX), a PET tracer for the A₁AR, we tested the hypothesis that hypoxia-induced adenosine release reduces A₁AR availability in the human brain. Furthermore, we investigated whether this response is associated with altered brain perfusion and psychomotor vigilance. Ten healthy volunteers completed a 110-min bolus–plus–constant-infusion [¹⁸F]CPFPX PET/MRI hybrid experiment including a 30-min interval of normobaric hypoxia with peripheral oxygen saturation between 70% and 75%. We obtained blood samples to calculate metabolite-corrected steady-state A₁AR distribution volumes and measured gray matter brain perfusion via arterial spin labeling in high temporal resolution. A 3-min psychomotor vigilance test was conducted every 10 min, and heart rate and peripheral blood oxygen saturation were continuously measured. <strong>Results:</strong> In all 7 examined brain regions, hypoxia reduced A₁AR availability significantly (e.g., frontal lobe, 13.5%; <em>P</em> = 0.0144) whereas gray matter brain perfusion increased (e.g., frontal lobe, 42.5%; <em>P</em> = 0.0007). Heart rate increased by 19% (<em>P</em> = 0.0039). Mean reaction speed decreased by 4.3% (<em>P</em> = 0.0021). <strong>Conclusion:</strong> Our study is the first, to our knowledge, to demonstrate that acute hypoxia, corresponding to a mean altitude of 5,500 m (18,000 ft), reduces A₁AR availability in the human brain. The finding is consistent with hypoxia-induced cerebral adenosine release leading to increased A₁AR occupancy.</p>","PeriodicalId":22820,"journal":{"name":"The Journal of Nuclear Medicine","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142816148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}