EJNMMI Radiopharmacy and Chemistry最新文献

{"title":"Preclinical evaluation of new GRPR-antagonists with improved metabolic stability for radiotheranostic use in oncology","authors":"Panagiotis Kanellopoulos,&nbsp;Adam Mattsson,&nbsp;Ayman Abouzayed,&nbsp;Karim Obeid,&nbsp;Berthold A. Nock,&nbsp;Vladimir Tolmachev,&nbsp;Theodosia Maina,&nbsp;Anna Orlova","doi":"10.1186/s41181-024-00242-6","DOIUrl":"10.1186/s41181-024-00242-6","url":null,"abstract":"<div><h3>Background</h3><p>The gastrin-releasing peptide receptor (GRPR) has been extensively studied as a biomolecular target for peptide-based radiotheranostics. However, the lack of metabolic stability and the rapid clearance of peptide radioligands, including radiolabeled GRPR-antagonists, often impede clinical application. Aiming at circumventing these drawbacks, we have designed three new GRPR-antagonist radioligands using [^99mTc]Tc-DB15 ([^99mTc]Tc-N₄-AMA-DIG-_DPhe-Gln-Trp-Ala-Val-Sar-His-Leu-NHEt; AMA: <i>p</i>-aminomethylaniline; DIG: diglycolate) as a motif, due to its high GRPR-affinity and stability to neprilysin (NEP). The new analogues carry the DOTAGA-chelator (1,4,7,10-tetraazacyclododecane-1-glutaric acid-4,7,10-triacetic acid) through different linkers at the N-terminus to allow for labeling with the theranostic radionuclide pair In-111/Lu-177. After labeling with In-111 the following radioligands were evaluated: (i) [¹¹¹In]In-AU-SAR-M1 ([¹¹¹In]In-DOTAGA-AMA-DIG-_DPhe-Gln-Trp-Ala-Val-Sar-His-Leu-NHEt), (ii) [¹¹¹In]In-AU-SAR-M2 ([¹¹¹In]In-[DOTAGA-Arg]AU-SAR-M1) and (iii) [¹¹¹In]In-AU-SAR-M3 ([¹¹¹In]In-[DOTAGA-_DArg]AU-SAR-M1).</p><h3>Results</h3><p>These radioligands were compared in a series of in vitro assays using prostate adenocarcinoma PC-3 cells and in murine models. They all displayed high and GRPR-specific uptake in PC-3 cells. Analysis of mice blood collected 5 min post-injection (pi) revealed similar or even higher metabolic stability of the new radioligands compared with [^99mTc]Tc-DB15. The stability could be further increased when the mice were treated with Entresto® to in situ induce NEP-inhibition. In PC-3 xenograft-bearing mice, [¹¹¹In]In-AU-SAR-M1 displayed the most favourable biodistribution profile, combining a good tumor retention with the highest tumor-to-organ ratios, with the kidneys as the dose-limiting organ.</p><h3>Conclusions</h3><p>These findings strongly point at AU-SAR-M1 as a promising radiotherapeutic candidate when labeled with Lu-177, or other medically appealing therapeutic radiometals, especially when combined with in situ NEP-inhibition. To this goal further investigations are currently pursued.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00242-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139745767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal administration enhances size-dependent pulmonary phagocytic uptake of poly(lactic-co-glycolic acid) nanoparticles","authors":"Seung Ho Baek,&nbsp;Eun-Ha Hwang,&nbsp;Gyeung Haeng Hur,&nbsp;Green Kim,&nbsp;You Jung An,&nbsp;Jae-Hak Park,&nbsp;Jung Joo Hong","doi":"10.1186/s41181-023-00227-x","DOIUrl":"10.1186/s41181-023-00227-x","url":null,"abstract":"<div><h3>Background</h3><p>Nanoparticles exhibit distinct behaviours within the body, depending on their physicochemical properties and administration routes. However, in vivo behaviour of poly(lactic-<i>co</i>-glycolic acid) (PLGA) nanoparticles, especially when administered nasally, remains unexplored; furthermore, there is a lack of comparative analysis of uptake efficiency among different administration routes. Therefore, here, we aimed to comprehensively investigate the real-time in vivo behaviour of PLGA nanoparticles across various administration routes. PLGA-NH₂ nanoparticles of three sizes were synthesised using an oil-in-water single-emulsion method. We assessed their uptake by murine macrophage RAW264.7 cells using fluorescence microscopy. To enable real-time tracking, we conjugated p-SCN-Bn-deferoxamine to PLGA-NH₂ nanoparticles and further radiolabelled them with ⁸⁹Zr-oxalate before administration to mice via different routes. Nanoparticle internalisation by lung immune cells was monitored using fluorescence-activated cell sorting analysis.</p><h3>Results</h3><p>The nanoparticle sizes were 294 ± 2.1 (small), 522.5 ± 5.58 (intermediate), and 850 ± 18.52 nm (large). Fluorescent labelling did not significantly alter the nanoparticle size and charge. The level of uptake of small and large nanoparticles by RAW264.7 cells was similar, with phagocytosis inhibition primarily reducing the internalisation of large particles. Positron emission tomography revealed that intranasal delivery resulted in the highest and most targeted pulmonary uptake, whereas intravenous administration led to accumulation mainly in the liver and spleen. Nasal delivery of large nanoparticles resulted in enhanced uptake by myeloid immune cells relative to lymphoid cells, whereas dendritic cell uptake initially peaked but declined over time.</p><h3>Conclusions</h3><p>Our study provides valuable insights into advancing nanomedicine and drug delivery, with the potential for expanding the clinical applications of nanoparticles.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-023-00227-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139734158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of an automated dispensing system for subsequent dose dispensing of different radionuclides","authors":"T. T. Cao,&nbsp;E. A. Aalbersberg,&nbsp;M. M. Geluk-Jonker,&nbsp;J. J. M. A. Hendrikx","doi":"10.1186/s41181-023-00228-w","DOIUrl":"10.1186/s41181-023-00228-w","url":null,"abstract":"<div><h3>Background</h3><p>Automated dispensing systems (ADSs) for radiopharmaceuticals have been developed to reduce the radiation exposure of personnel, to improve the accuracy of the dispensed dose and to limit the microbiological contamination. However, before implementing such systems, validation according to various applicable guidelines is necessary to ensure safety and quality. Here we present the selection, validation and implementation of the PT459R2 from manufacturer Lynax s.r.o. as a guidance protocol for validation according to GMP and GRPP guidelines. Validation included linearity accuracy and precision of the internal scintillation detector for different isotopes and microbiological validation for aseptic procedures.</p><h3>Results</h3><p>The ADS can dispense accurate doses in the following linear range: 1000–10,000 MBq for lutetium-177, 20–74 MBq for zirconium-89, 100–1000 MBq for gallium-68 and 100–2000 MBq for fluorine-18. The maximum bias is 2.35% and the maximum coefficient of variation is 3.03% which meets the acceptance criteria of &lt; 5%. Furthermore, the ADS does not affects the GMP class A environment in a laminar airflow cabinet and can dispense aseptically. In addition, radiation exposure is acceptable and data integrity is preserved.</p><h3>Conclusion</h3><p>The PT459R2 ADS met all the requirements from our performance qualification and is therefore suitable for daily routine use in our center. Our approach can be used as a guidance for PQ of an ADS in a Radiopharmacy according to GMP and GRPP guidelines.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-023-00228-w","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139721067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved synthesis of 6-bromo-7-[11C]methylpurine for clinical use","authors":"Toshimitsu Okamura,&nbsp;Tatsuya Kikuchi,&nbsp;Masanao Ogawa,&nbsp;Ming-Rong Zhang","doi":"10.1186/s41181-024-00240-8","DOIUrl":"10.1186/s41181-024-00240-8","url":null,"abstract":"<div><h3>Background</h3><p>Multidrug resistance-associated protein 1 (MRP1), an energy-dependent efflux pump, is expressed widely in various tissues and contributes to many physiological and pathophysiological processes. 6-Bromo-7-[¹¹C]methylpurine ([¹¹C]7m6BP) is expected to be useful for the assessment of MRP1 activity in the human brain and lungs. However, the radiochemical yield (RCY) in the synthesis of [¹¹C]7m6BP was low, limiting its clinical application, because the methylation of the precursor with [¹¹C]CH₃I provided primarily the undesired isomer, 6-bromo-9-[¹¹C]methylpurine ([¹¹C]9m6BP). To increase the RCY of [¹¹C]7m6BP, we investigated conditions for improving the [¹¹C]7m6BP/[¹¹C]9m6BP selectivity of the methylation reaction.</p><h3>Results</h3><p>[¹¹C]7m6BP was manually synthesized via the methylation of 6-bromopurine with [¹¹C]CH₃I in various solvents and at different temperatures in the presence of potassium carbonate for 5 min. Several less polar solvents, including tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), and ethyl acetate (AcOEt) improved the [¹¹C]7m6BP/[¹¹C]9m6BP selectivity from 1:1 to 2:1, compared with the conventionally used solvents for the alkylation of 6-halopurines, acetone, acetonitrile, and <i>N</i>,<i>N</i>-dimethylformamide. However, a higher temperature (140 °C or 180 °C) was needed to progress the ¹¹C-methylation in the less polar solvents, and the manual conditions could not be directly translated to an automated synthesis. [¹¹C]Methyl triflate ([¹¹C]CH₃OTf) was thus used as a methylating agent to increase the conversion at a lower temperature. The ¹¹C-methylation using [¹¹C]CH₃OTf at 100 °C proceeded efficiently in THF, 2-MeTHF, and AcOEt with maintenance of the improved selectivity. Starting from 28 to 34 GBq [¹¹C]CO₂, [¹¹C]7m6BP was produced with 2.3–2.6 GBq for THF, 2.7–3.3 GBq for AcOEt, and 2.8–3.9 GBq for 2-MeTHF at approximately 30 min after the end of bombardment (<i>n</i> = 3 per solvent). The isolated RCYs (decay corrected) for THF, 2-MeTHF, and AcOEt were 24–28%, 29–35%, and 22–31% (<i>n</i> = 3), respectively.</p><h3>Conclusions</h3><p>The use of THF, 2-MeTHF, and AcOEt improved the [¹¹C]7m6BP/[¹¹C]9m6BP selectivity in the methylation reaction, and the improved method provided [¹¹C]7m6BP with sufficient radioactivity for clinical use.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-02-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00240-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139705704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Implementing Ac-225 labelled radiopharmaceuticals: practical considerations and (pre-)clinical perspectives","authors":"Eline L. Hooijman,&nbsp;Valery Radchenko,&nbsp;Sui Wai Ling,&nbsp;Mark Konijnenberg,&nbsp;Tessa Brabander,&nbsp;Stijn L. W. Koolen,&nbsp;Erik de Blois","doi":"10.1186/s41181-024-00239-1","DOIUrl":"10.1186/s41181-024-00239-1","url":null,"abstract":"<div><h3>Background</h3><p>In the past years, there has been a notable increase in interest regarding targeted alpha therapy using Ac-225, driven by the observed promising clinical anti-tumor effects. As the production and technology has advanced, the availability of Ac-225 is expected to increase in the near future, making the treatment available to patients worldwide.</p><h3>Main body</h3><p>Ac-225 can be labelled to different biological vectors, whereby the success of developing a radiopharmaceutical depends heavily on the labelling conditions, purity of the radionuclide source, chelator, and type of quenchers used to avoid radiolysis. Multiple (methodological) challenges need to be overcome when working with Ac-225; as alpha-emission detection is time consuming and highly geometry dependent, a gamma co-emission is used, but has to be in equilibrium with the mother-nuclide. Because of the high impact of alpha emitters in vivo it is highly recommended to cross-calibrate the Ac-225 measurements for used quality control (QC) techniques (radio-TLC, HPLC, HP-Ge detector, and gamma counter). More strict health physics regulations apply, as Ac-225 has a high toxicity, thereby limiting practical handling and quantities used for QC analysis.</p><h3>Conclusion</h3><p>This overview focuses specifically on the practical and methodological challenges when working with Ac-225 labelled radiopharmaceuticals, and underlines the required infrastructure and (detection) methods for the (pre-)clinical application.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00239-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139690897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of 68Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography","authors":"Lei Wang,&nbsp;Hsiou-Ting Kuo,&nbsp;Zhengxing Zhang,&nbsp;Chengcheng Zhang,&nbsp;Chao-Cheng Chen,&nbsp;Devon Chapple,&nbsp;Ryan Wilson,&nbsp;Nadine Colpo,&nbsp; François Bénard,&nbsp;Kuo-Shyan Lin","doi":"10.1186/s41181-024-00241-7","DOIUrl":"10.1186/s41181-024-00241-7","url":null,"abstract":"<div><h3>Background</h3><p>Overexpressed in various solid tumors, gastrin-releasing peptide receptor (GRPR) is a promising cancer imaging marker and therapeutic target. Although antagonists are preferable for the development of GRPR-targeted radiopharmaceuticals due to potentially fewer side effects, internalization of agonists may lead to longer tumor retention and better treatment efficacy. In this study, we systematically investigated unnatural amino acid substitutions to improve in vivo stability and tumor uptake of a previously reported GRPR-targeted agonist tracer, [⁶⁸Ga]Ga-TacBOMB2 (⁶⁸Ga-DOTA-Pip-D-Phe⁶-Gln⁷-Trp⁸-Ala⁹-Val¹⁰-Gly¹¹-His¹²-Leu¹³-Thz¹⁴-NH₂).</p><h3>Results</h3><p>Unnatural amino acid substitutions were conducted for Gln⁷, Trp⁸, Ala⁹, Val¹⁰, Gly¹¹ and His¹², either alone or in combination. Out of 25 unnatural amino acid substitutions, <i>tert</i>-Leu¹⁰ (Tle¹⁰) and NMe-His¹² substitutions were identified to be preferable modifications especially in combination. Compared with the previously reported [⁶⁸Ga]Ga-TacBOMB2, the Tle¹⁰ and NMe-His¹² derived [⁶⁸Ga]Ga-LW01110 showed retained agonist characteristics and improved GRPR binding affinity (K_i = 7.62 vs 1.39 nM), in vivo stability (12.7 vs 89.0% intact tracer in mouse plasma at 15 min post-injection) and tumor uptake (5.95 vs 16.6 %ID/g at 1 h post-injection).</p><h3>Conclusions</h3><p>Unnatural amino acid substitution is an effective strategy to improve in vivo stability and tumor uptake of peptide-based radiopharmaceuticals. With excellent tumor uptake and tumor-to-background contrast, [⁶⁸Ga]Ga-LW01110 is promising for detecting GRPR-expressing cancer lesions with PET. Since agonists can lead to internalization upon binding to receptors and foreseeable long tumor retention, our optimized GRPR-targeted sequence, [Tle¹⁰,NMe-His¹²,Thz¹⁴]Bombesin(7–14), is a promising template for use for the design of GRPR-targeted radiotherapeutic agents.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00241-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139669257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel PSMA-targeting tracer with highly negatively charged linker demonstrates decreased salivary gland uptake in mice compared to [68Ga]Ga-PSMA-11","authors":"Steve S. Huang,&nbsp;Frank P. DiFilippo,&nbsp;Daniel J. Lindner,&nbsp;Warren D. Heston","doi":"10.1186/s41181-024-00237-3","DOIUrl":"10.1186/s41181-024-00237-3","url":null,"abstract":"<div><h3>Background</h3><p>The current generation of radiolabeled PSMA-targeting therapeutic agents is limited by prominent salivary gland binding, which results in dose-limiting xerostomia from radiation exposure. JB-1498 is a urea-based small molecule with a highly negatively charged linker targeting prostate specific membrane antigen (PSMA). Prior work on a similar tracer with the same negatively charged linker demonstrated low normal organ/soft tissue background uptake compared to [⁶⁸Ga]Ga-PSMA-11. The purpose of this study was to investigate if [⁶⁸Ga]Ga-JB-1498 had reduced salivary gland uptake in mice compared to [⁶⁸Ga]Ga-PSMA-11.</p><h3>Results</h3><p>JB-1498 demonstrated high affinity for PSMA binding and tumor uptake in a murine tumor model. In an initial biodistribution study with low molar activity, [⁶⁸Ga]Ga-JB-1498 demonstrated salivary gland uptake of 0.13 ± 0.01%ID/g. In a second biodistribution study in non-tumor-bearing mice with high molar activity, [⁶⁸Ga]Ga-JB1498 demonstrated salivary gland uptake of 0.39 ± 0.24% ID/g and kidney activity of 10.12 ± 1.73% ID/g at one hour post IV injection. This salivary gland uptake is significantly less than the published uptake of [⁶⁸Ga]Ga-PSMA-11. Micro-PET visually confirmed the findings of the biodistribution studies. Dynamic micro-PET imaging demonstrated gradually decreasing [⁶⁸Ga]Ga-JB1498 activity in salivary glands and kidneys, compared to gradually increasing [⁶⁸Ga]Ga-PSMA-11 activity in these two organs during the first hour.</p><h3>Conclusion</h3><p>Biodistribution and micro-PET imaging of [⁶⁸Ga]Ga-JB-1498 demonstrate significantly decreased salivary gland uptake and different pharmacokinetic behavior in kidneys and salivary glands in mice compared to [⁶⁸Ga]Ga-PSMA-11. Our findings suggest that constructing a PSMA-targeting molecule with a highly negatively charged linker is a promising strategy to reduce salivary gland uptake of GCP-II/PSMA ligands in theranostic applications.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-024-00237-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139574432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically based radiopharmacokinetic (PBRPK) modeling to simulate and analyze radiopharmaceutical therapies: studies of non-linearities, multi-bolus injections, and albumin binding","authors":"Ali Fele-Paranj,&nbsp;Babak Saboury,&nbsp;Carlos Uribe,&nbsp;Arman Rahmim","doi":"10.1186/s41181-023-00236-w","DOIUrl":"10.1186/s41181-023-00236-w","url":null,"abstract":"<div><h3>Background</h3><p>We aimed to develop a publicly shared computational physiologically based pharmacokinetic (PBPK) model to reliably simulate and analyze radiopharmaceutical therapies (RPTs), including probing of hot-cold ligand competitions as well as alternative injection scenarios and drug designs, towards optimal therapies.</p><h3>Results</h3><p>To handle the complexity of PBPK models (over 150 differential equations), a scalable modeling notation called the “reaction graph” is introduced, enabling easy inclusion of various interactions. We refer to this as physiologically based radiopharmacokinetic (PBRPK) modeling, fine-tuned specifically for radiopharmaceuticals. As three important applications, we used our PBRPK model to (1) study the effect of competition between hot and cold species on delivered doses to tumors and organs at risk. In addition, (2) we evaluated an alternative paradigm of utilizing multi-bolus injections in RPTs instead of prevalent single injections. Finally, (3) we used PBRPK modeling to study the impact of varying albumin-binding affinities by ligands, and the implications for RPTs. We found that competition between labeled and unlabeled ligands can lead to non-linear relations between injected activity and the delivered dose to a particular organ, in the sense that doubling the injected activity does not necessarily result in a doubled dose delivered to a particular organ (a false intuition from external beam radiotherapy). In addition, we observed that fractionating injections can lead to a higher payload of dose delivery to organs, though not a differential dose delivery to the tumor. By contrast, we found out that increased albumin-binding affinities of the injected ligands can lead to such a differential effect in delivering more doses to tumors, and this can be attributed to several factors that PBRPK modeling allows us to probe.</p><h3>Conclusions</h3><p>Advanced computational PBRPK modeling enables simulation and analysis of a variety of intervention and drug design scenarios, towards more optimal delivery of RPTs.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10803696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139511202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical evaluation of the theranostic potential of 89Zr/177Lu-labeled anti-TROP-2 antibody in triple-negative breast cancer model","authors":"Yitian Wu,&nbsp;Tuo li,&nbsp;Xianzhong Zhang,&nbsp;Hongli Jing,&nbsp;Fang Li,&nbsp;Li Huo","doi":"10.1186/s41181-023-00235-x","DOIUrl":"10.1186/s41181-023-00235-x","url":null,"abstract":"<div><h3>Background</h3><p>Triple-negative breast cancer (TNBC) is one of the most lethal malignant tumors among women, characterized by high invasiveness, high heterogeneity, and lack of specific therapeutic targets such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Trophoblast cell-surface antigen-2 (TROP-2) is a transmembrane glycoprotein over-expressed in 80% of TNBC patients and is associated with the occurrence, progress, and poor prognosis of TNBC. The TROP-2 targeted immunoPET imaging allows non-invasive quantification of the TROP-2 expression levels of tumors, which could help to screen beneficiaries most likely to respond to SG and predict the response. This study aimed to develop a ⁸⁹Zr/¹⁷⁷Lu-radiolabeled anti-TROP-2 antibody (NY003) for immunoPET and SPECT imaging, as well as radioimmunotherapy (RIT) in TROP-2 (+)TNBC tumor-bearing model. Based on the camelid antibody, we developed a TROP-2 targeted recombinant antibody NY003. NY003 was conjugated with DFO and DTPA for ⁸⁹Zr and ¹⁷⁷Lu radiolabelling, respectively. The theranostic potential of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003 was evaluated through immunoPET, SPECT imaging, and RIT studies in the subcutaneous TROP-2 positive TNBC xenograft mice model.</p><h3>Results</h3><p>The high binding affinity of NY003 to TROP-2 was verified through ELISA. The radiochemical purity of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003 exceeded 95% and remained stable within 144h p.i. in vitro. ImmunoPET and SPECT imaging showed the specific accumulation of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003 in MDA-MB-231 tumors and gradually increased with the time tested, significantly higher than that in control groups (<i>P</i> &lt; 0.05). The strongest anti-tumor efficacy was observed in the high-dose of [¹⁷⁷Lu]Lu-DTPA-NY003 group, followed by the low-dose group, the tumor growth was significantly suppressed by [¹⁷⁷Lu]Lu-DTPA-NY003, the tumor volumes of both high- and low-dose groups were smaller than the control groups (<i>P</i> &lt; 0.05). Ex vivo biodistribution and histological staining verified the results of in vivo imaging and RIT studies.</p><h3>Conclusion</h3><p>As a drug platform for radiotheranostics, ⁸⁹Zr/¹⁷⁷Lu-radiolabeled anti-TROP-2 antibody NY003 could not only non-invasively screen the potential beneficiaries for optimizing SG ADC treatment but also suppressed the growth of TROP-2 positive TNBC tumors, strongly supporting the theranostic potential of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-023-00235-x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139401297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cu(II)-Mediated direct 18F-dehydrofluorination of phosphine oxides in high molar activity","authors":"Xiaoqun Tang,&nbsp;Shengji Lv,&nbsp;Zhaobiao Mou,&nbsp;Xia Liu,&nbsp;Zijing Li","doi":"10.1186/s41181-023-00234-y","DOIUrl":"10.1186/s41181-023-00234-y","url":null,"abstract":"<div><h3>Background</h3><p>The ¹⁸F/¹⁹F-isotope exchange method employing P(V)-centered prosthetic groups demonstrates advantages in addressing mild one-step aqueous ¹⁸F-labeling of peptides and proteins. However, the molar activity (A_m) achieved through isotope exchange remains relatively low, unless employing a high initial activity of [¹⁸F]F⁻. To overcome this drawback, our work introduces a novel approach through a Cu-mediated direct ¹⁸F-dehydrofluorination of phosphine oxides. This method leverages the straightforward separation of the ¹⁸F-labeled product from the phosphine oxide precursors, aiming to primarily increase A_m.</p><h3>Results</h3><p>Through a ¹⁹F-dehydrofluorination efficiency test, Cu(OAc)₂ was identified as the optimal oxidative metal salt, exhibiting a remarkable 100% conversion within one hour. Leveraging the straightforward separation of phosphine oxide precursors and phosphinic fluoride products, the A_m of an activated ester, [¹⁸F]<b>4</b>, sees an impressive nearly 15-fold increase compared to the ¹⁸F/¹⁹F-isotope exchange, with the same initial activity of [¹⁸F]F⁻. Furthermore, this Cu(II)-mediated ¹⁸F-dehydrofluorination approach demonstrates tolerance up to 20% solvent water content, which enables the practical radiosynthesis of ¹⁸F-labeled water-soluble molecules under non-drying conditions.</p><h3>Conclusions</h3><p>The direct ¹⁸F-dehydrofluorination of phosphine oxide prosthetic groups has been successfully accomplished, achieving a high A_m via Cu(II)-mediated oxidative addition and reductive elimination.</p></div>","PeriodicalId":534,"journal":{"name":"EJNMMI Radiopharmacy and Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.6,"publicationDate":"2024-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ejnmmipharmchem.springeropen.com/counter/pdf/10.1186/s41181-023-00234-y","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139110632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}