DFT study of molecular probe release process of Ln-DOTA (Eu, Gd, Tb) ester complexes

DFT study of molecular probe release process of Ln-DOTA (Eu, Gd, Tb) ester complexes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article DFT study of molecular probe release process of Ln-DOTA (Eu, Gd, Tb) ester complexes Xinghui Zhang, Haipeng Shi, Yongning Yuan, Jianyi Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7254638/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Context Ln DOTA has been proven to have important application value in clinical medicine schools. Recently, there have been experimental reports on its probe hydrolysis release process. In order to clarify the specific micro reaction mechanism and the influencing factors of hydrolysis activity, this paper uses computational chemistry methods to systematically calculate and investigate the release reaction mechanism and hydrolytic activity of lanthanide ester complexes Ln-DOTA molecular probes under alkaline conditions. Different alcohol-based substituents NB, NI, Bn and lanthanide metal centers (Ln = Eu, Gd, Tb) were selected as reactants to complete the calculation research under the corresponding experimental conditions. The calculated results showed that this reaction includes three possible steps: the nucleophilic attack of the ester carbon atom, the dissociation of the alcohol group the ester bond, and the hydrogen transfer to the alcohol group, and finally the release process is completed to obtain the DOTA product. The activation energies are low (G < 5.75 kcal/mol) and the lanthanide metal center and different substituents have influence, but minor changes do not have a significant effect on the reaction mechanism and activity, indicating that it is easy to accomplish the hydrolytic release of lanthanide complexes under the existing mild experimental conditions, which is consistent with the results of experimental research. Meanwhile, the computational research also provides important basis for further exploring the mechanism of such reactions. Methods The geometry optimization and electronic properties calculations based on density functional theory were performed using the PBE1PBE method. All the theoretical calculations in this work were performed using the Gaussian 09 software. The lanthanide atoms Eu, Gd, and Tb are calculated using effective core pseudopotentials (RECPs) with 52–54 core electrons, while other atoms are selected from the 6-311G (d, p) basis group. Accurate free energy calculations were performed using the SMD solvent model at the PBE0/def2TZVP theoretical level. Lanthanide complexes hydrolysis process Ln-DOTA probe PBE0 calculation method Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 1. Introduction Hepatocellular carcinoma (HCC), as the third leading cause of death from malignant tumors globally, poses a significant to human health and severely affects the quality of life and survival time of patients. The implementation of early detection of HCC, strengthening early identification, diagnosis, and intervention, is important way to improve the success rate of treatment and extend the survival time of patients[ 1 – 4 ]. Magnetic resonance imaging (MRI) is a non-invasive, high-resolution imaging that has become an important tool for clinical diagnosis and has a higher sensitivity and specificity in detecting malignant and benign liver lesions [ 5 , 6 ]. MRI has significant advantages in the field of medical because of its characteristics such as no ionizing radiation, high soft tissue contrast, multiple sequences, and multi-plane imaging [ 7 ]. Also, in order to further improve the sensitivity of conventional, some clinical MRI imaging uses contrast agents to enhance the imaging, which can provide more morphological and functional information. It not only increases the contrast between the accumulation area and the background but can also further enhance the contrast of the image by affecting the relaxation process of water protons in the surrounding tissues, thereby improving the accuracy of disease diagnosis. This molecular imaging principle of great significance for achieving accurate diagnosis and targeted treatment [ 8 , 9 ]. Lanthanide complexes have been shown to be a good alternative to organic fluorophores due to their long emission lifetimes and sharp emission bands, which enable elimination of biological autofluorescence and scattering light by time-control techniques [ 10 , 11 ]. Luminescent lanthanide complexes can also be used as ideal MRI contrast agents by tuning the parameters of the complexes to change the MRI signal intensity and the water relaxation rate. Therefore, lanthanide complexes have unique advantages for designing responsive probes to monitor the changes of bothinescence and MRI contrast in the same system [ 12 – 16 ]. Currently, gadolinium (III) contrast agents(CA) are considered the workhorses of this diagnostic imaging technique [ 17 – 19 ]. The contrast agents of gadolinium are generally by the combination of Gd (III) with organic ligands to form stable organic complexes that can be excreted from the body after intravenous injection. It occupies special position in MRI and is widely used in clinics for the detection and diagnosis of cancer, infection, hemorrhage, and nervous system diseases, etc. In the molecular probe design of clinical application, the chelates formed by the cage-like small molecule DTPA and DOTA with multi-coordination witholinium ions are the best method at present. The connection of Gd 3+ with polyamino carboxylic acid ligands (including DOTA, DOTPA, DO3A, DTTA, DTPA and EDTA) has strong stability and low toxicity, and can enhance the intensity of CA in MRI signal [ 20 – 22 ]. In 2018, the research team of Liu and Nazare [ 23 ] designed and explored the MRI contrast agent, a nitrobenzyl -substituted gadolinium complex, G-DOTA-PNB. The probe can be activated to the Gd-DOTA in the environment of nitroreductase (NTR), which can detect NTR by enhancing the contrast performance. Recently, Foster et al. Reported [ 24 ] the synthesis of similar lanthanide complexes probe, which was extended to the europium, gadolinium and terbium elements, and the corresponding complexes with single ester formed by groups such as nitrophenyl, imidazolyl, phenyl, etc. These esters were activated under alkaline conditions to generate the corresponding DOTA complexes (Scheme 1 ), and the changes of their optical and relaxation properties were tested, and the results were well studied. The experimental process of activated release was found to have added ethanol solvent, and it could be easily completed at 40℃. In order to deeply the microscopic mechanism and reaction activity of the reaction process, this paper uses the PBE1PBE method of density functional theory to calculate and study the possible structure of the reaction, explore and analyze its microscopic state of activated reaction process, reaction activity and the influence of its metal center and organic group on the change. 2. Computational details All the theoretical calculations in this work were performed using the Gaussian 09 software [ 25 ]. The PBE1PBE computational method [ 26 ] of the PBE0 was employed to perform the geometric configuration optimization and vibrational frequency calculations for lanthanide complexes and ligands in the gas phase and in solvent, with the DFT-D3(BJ) correction[ 27 – 28 ] applied to the systems under investigation. The PBE0 functional has been shown to provide reasonable and reliable results for lanthanide and actinide [ 29 – 32 ]. For lanthanides Eu, Gd, and Tb, the 52–54 core electrons of the atoms were treated with effective core pseudo potentials (RECPs) [ 33 – 34 ], using ECP52MWB-SEG, ECP53MWB-SEG, ECP54B-SEG as corresponding valence basis sets. For other light elements C, H, N, and O, the 6-311G(d,p) basis set was used. All the stationary structures were verified by vibrational frequency analysis, the intermediate has no negative eigenvalues, and the transition state structure has only one negative. To approximate the experimental environment and obtain more accurate energies, the solvent effect of the reaction was considered using the SMD solvation model [ 35 , 36 ], ethanol was selected as solvent, and the Gibbs free energies of the solvent process were obtained at the PBE0/def2TZVP theoretical level [ 37 ]. The intrinsic reaction coordinate (IRC) calculation [ 38 ] was performed to ensure that each transition state structure was connected to the corresponding two stable structures on the reaction path. The wave function analysis was performed using Multiwfn 3.8 software package[ 39 ], and the 3D figures were drawn using the Gauss View [ 40 ] and CYLview software [ 41 ]. 3. Result and discussion Based on the experimental research of Foster and Sneddon et al. [ 24 ] and the possible mechanism of ester hydrolysis under alkaline conditions, a potential pathway for system was proposed in this paper, combined with the reaction in Scheme 1 . The reaction is an S N1 nucleophilic substitution reaction with a two-step process. n the first step, the nucleophile attacks the C atom in the ester. The second step of the reaction is the departure of the leaving group from the compound. 3.1 Alkaline hydrolysis of the nitrobenzyl monoester of the Eu complex In the reaction of Scheme 1 , firstly, the lanthanide metal center was selected as europium, and 4-nitrobenzeneNb) was selected as the research object to undergo hydrolysis process under alkaline conditions. The specific reaction path is shown in Fig. 1 , and the geometries of the various stationary points with key structural parameters are given in Fig. 2 . It can be seen from Fig. 1 that the intermediate Eu-1a is formed first by the attack reaction of OH − on the central atom Eu of substrate R. This step decreases the energy by 5.35 kcal/mol. In Eu-1a, the newly formed Eu-O 3 bond length is 2.229 Å, and the Eu-O 1 is completely dissociated. Subsequently, the OH nucleophile in Eu-1a attacks the C atom in the ester bond of this molecule through the transition state Eu-tsa1 to form the intermediate Eu-2a. In Eu-tsa1, the O 3 -C bond length is 2.310 Å, and the ester C atom changes from sp 2 to sp 3 hybridization during the process from Eu-1a to Eu-2a. The activation free energy of this step is 3.07 kcal/mol, and the intermediate Eu-2a is 10.63 kcal/mol lower in energy than Eu-1a, and its stability is enhanced. Then, the leaving group 4-nitrobenzyloxy dissociates from the ester bond to form the carboxylic acid intermediate Eu-3a, in which the O atom of the leaving group is coordinated to the Eu center atom. In Eu-tsa2, the distance between dissociated C and O 2 is 1.800 Å, and O 2 is also bonded to the Eu atom with a bond length of 2.349 Å. The ester group carbon atom reverts to sp 2 hybridization. The relative free energy from Eu-2a to Eu-tsa2 is 12.85 kcal/mol, and the free energy of Eu-3a is 5.83 kcal/mol higher than that of Eu-2a, indicating that this step is an endothermic process. The last step is the hydrogen transfer from the carboxylic acid to the benzyl alcohol through the Eu-tsa3 transition state, giving product of Eu-DOTA complex Eu-4a and p-nitrobenzyl alcohol. In Eu-4a, the carboxylic oxygen atom that transfers the lost hydrogen atom coordinates to Eu atom at the center of the complex. The activation free energy of this step is 4.9 kcal/mol, which is also a strong exothermic process, and its value is 23.40 kcal/mol. The whole reaction a relatively low activation energy, and the reaction is easily completed under the experimental condition of 40 ℃, and the overall reaction is exothermic 33.5 kcal/mol. This provides a good mechanistic complement and microscopic explanation for experimental research [ 24 ]. 3.2 The influence of different reactant ligands and metal centers on the activation of hydrolysis reaction 3.2.1 Different reactant ligands Based on the experimental research of Foster et al.[ 24 ], this paper selects different reactant ligands of 1-methyl-2-nitroimidaz(NI) and phenyl(Bn) to replace 4-nitrobenzyl(NB) for similar mechanism research under the condition of constant Eu central. The relevant coordinates of the specific stationary structures are given in the Supporting Information. The possible pathways for hydrolysis reaction of the three different reaction substrates are shown in Fig. 3 as an energy profile, where pathways a, b, c are the substituents of the substrate NB, NI, Bn, respectively. Comparison of the channels of three reactants, the trend of the energy curve is basically the same. It can be seen from Fig. 3 that the energies of the first and second transition states are lower than those of the reactants, and the three substrates are relatively close, Eu-tsa1 to Eu-tsc1 is -2.28 to 2.04 kcal/mol, and Eu-ts (a2-c2) is -4.03 to -1.57 kcal/mol. However, in the third transition state, channel b has a significantly higher energy than channels a and c, with the relationship being Eu-tsb3(5.75 kcal/mol) > Eu-tsc3(-1.98 kcal/mol) > Eu-tsa3(-5.36kcal/mol). Overall, the three reactions have low activation energies and are easily achieved under experimental conditions. Moreover, they are all strong exothermic processes, with the release of heat from 31.94 to 33.55 kcal/mol. At the same time, the frontier molecular orbitals of three reactant structures were calculated and investigated on the same theoretical level, and the specific frontier molecular orbitals (HOMO and LUMO) diagram and orbital energy level are shown in Fig. 4 . The energies of the frontier molecular orbitals increase in the order R-a, R-b, R-c with the values of 0.1588 0.1638, and 0.1996 eV, respectively, which is also consistent with the three activation energies of the first step of the reaction in order. The projected plots of the electronic localization function (ELF) and the localized-orbital locator (LOL) also present the charge density and charge distribution in the molecular intuitively. 3.2.2 The influence of metal center To further explore the effect of different metal centers on the reactivity, subsequent systematic calculations were performed by choosing Gd and Tb to replace the Eu atom reactant R in channel a, respectively. The calculated energy barriers are shown in Fig. 5 , and the Cartesian coordinates of the structures are shown in the Supporting Information. The calculated results show that the hydrolysis process of Gd and Tb metal complexes has three processes similar to Eu metal complexes, i.e. the alkaline nucleophile attacks the ester C atom, the ester bond dissociates the leaving group of alcohol, and the hydrogen transfer to obtain the DOTA complex. Moreover, the relative activation free energies of the three reactants are close to each other and also low. The first step is the rate-determining step of the whole reaction and the activation energy relationship is G Tb (6.48 kcal/mol) > G Gd (6.02 kcal/mol) > G Eu (3.07 kcal/mol). Since Eu, Gd, and Tb are lanthanide elements, they have similar chemical properties, and the small energy gap calculated can also predict the corresponding lanthanide complexes have similar reaction channels, and it is easy to carry out in the experiment, that is, the reaction activity of lanthanide metal center little effect on this hydrolysis reaction. 4. Conclusion In this work, the process of hydrolytic release in alkaline condition of the complex molecular probe of lanthanide DOTA ester was systematically investigated by using PBE0 calculation method of DFT. According to the theoretical calculation results, the following conclusion can be drawn: (1) From the analysis of the potential energy surface and the main configurations, it is clear that the complex probe undergoes three possible steps in the hydrolytic in an alkaline environment, i.e., the nucleophile attacks the ester C atom, the ester bond dissociates the leaving group of the alcohol, the hydrogen transfer completes the release to obtain the DOTA complex. (2) Comparing the three different alcohol substituents of the reactant, the NI group has a relatively high activation energy in the final hydrogen transfer, but overall activation energies are all low, it indicates that this reaction can be easily achieved under experimental conditions. (3) Different lanthanide metal centers have little effect on the hydrolytic activity of the reaction complex. (4) This computational study can provide a very valuable complement to the experimental study of the Foster research team, and also provide an important reference for the mechanistic of the hydrolysis reaction of other lanthanide or transition metal complexes. Declarations Supporting information Supporting information includes the Cartesian coordinates of all structures reported in this work. Acknowledgments We sincerely thank the National Natural Science Foundation of China, the Natural Science Foundation of Gansu Province, and Lanzhou University of Arts and Sciences for their strong support. We are grateful to the reviewers for their invaluable suggestions. Author contributions Xinghui Zhang: problem selection, writing, and data analysis. Haipeng Shi: simulations, result analysis, manuscript first draft. Yongning Yuan: methods, project management, result analysis, manuscript editing. Jianyi Wang: data analysis, writing. Funding This work was supported by the Outstanding Youth Research Program of Lanzhou University of Arts and Sciences (2021SZZX06 ), Natural Science Foundation of Gansu Province (20JR5RA479), National Natural Science Foundation of China (22165017). Data Availability No datasets were generated or analysed during the current study. Ethics approval NA. Consent to participate NA. Consent for publication Written informed consent for publication was obtained from all participants. Conflict of interest The authors declare no competing interests. References Talesh GA, Trézéguet V, Merched A(2020)Hepatocellular carcinoma and statins. 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Phys Chem Chem Phys 7:3297–3305. https://doi.org/10.1039/B508541A Gonzalez C, Schlegel HB (1989) An improved algorithm for reaction path following. J Chem Phys 90: 2154–2161. https://doi.org/10.1063/1.456010 Lu T, Chen F (2012) Multiwfn: a multifunctional wavefunction analyzer. Journal of Computational Chemistry, 33:580–592. https://onlinelibrary.wiley.com/doi/ 10.1002/jcc.22885 Dennington R, Keith T, Millam J (2009) GaussView, version 5. Semichem Inc., Shawnee Mission, KS. Legault CY (2009) CYLview, 1.0b. Université de Sherbrooke: Sherbrooke, Quebec, Canada. http://www.cylview.org/ Schemes Scheme 1 is available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Supportinginformation.doc Scheme1.png Scheme 1. The DOTA monoesters of lanthanide complexes (Ln = Eu, Gd, Tb) hydrolyze under alkaline conditions to form the corresponding DOTA complexes. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7254638","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":493871561,"identity":"7f8f9df1-158a-4b18-be99-7090b6b6c315","order_by":0,"name":"Xinghui Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuklEQVRIie3PsQrCMBDG8QuBcwnO52J8hIpQHHyYK0K7tHt3IVNxFhR9C+cUoZM+gQ4VwWfIJIKbgzTdHPKb78/HAQTBPyJAYPca42BleyT3ys6GqmH/RLRokz3lE79Cb6u4ZXXLDOQArjx2J2LXZBHPn4WBixXV+dqdSFo2xEoWRqxZCuORICWGGGWGUkV+ifqs4IkRfROiNKWkSqdGIddev+hNHo+cW2h9eNStKz2SL7bnfRAEQfDLG4ZVOCq7i117AAAAAElFTkSuQmCC","orcid":"","institution":"Lanzhou University of Arts and Science","correspondingAuthor":true,"prefix":"","firstName":"Xinghui","middleName":"","lastName":"Zhang","suffix":""},{"id":493871562,"identity":"7069f654-da2f-42fe-b82f-6dcdb877f0dc","order_by":1,"name":"Haipeng Shi","email":"","orcid":"","institution":"Sinopec Nanjing Engineering Co., Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Haipeng","middleName":"","lastName":"Shi","suffix":""},{"id":493871565,"identity":"8e1b5bfe-c929-4363-96b9-5d71117d98d7","order_by":2,"name":"Yongning Yuan","email":"","orcid":"","institution":"Lanzhou University of Arts and Science","correspondingAuthor":false,"prefix":"","firstName":"Yongning","middleName":"","lastName":"Yuan","suffix":""},{"id":493871566,"identity":"4dcf5dbe-2f00-47b3-a30e-c5278e9e94f8","order_by":3,"name":"Jianyi Wang","email":"","orcid":"","institution":"Lanzhou University of Arts and Science","correspondingAuthor":false,"prefix":"","firstName":"Jianyi","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-07-30 15:53:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7254638/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7254638/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88332762,"identity":"b1616f05-a12c-4c25-945e-b58eccf9975c","added_by":"auto","created_at":"2025-08-05 11:09:34","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":69311,"visible":true,"origin":"","legend":"\u003cp\u003eFull energy profile for the alkaline hydrolysis of the nitrobenzyl monoester of Eu complexes containing DOTA，Relative energies are in kcal/mol.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7254638/v1/f2d827dca67ce6fbab7e00ad.png"},{"id":88332768,"identity":"7fec66dc-0867-4fb1-ba3b-292040516dd2","added_by":"auto","created_at":"2025-08-05 11:09:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":165293,"visible":true,"origin":"","legend":"\u003cp\u003eGeometry of the main intermediates and transition states selected for the Eu-a channel. epresentative bond lengths are in Å.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7254638/v1/d150fe6d8ad21719cc73d31c.png"},{"id":88332767,"identity":"5133650b-8ab9-41ef-8253-4f90cf5da8af","added_by":"auto","created_at":"2025-08-05 11:09:34","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":25492,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of energy barriers for the three reaction channels of ester hydrolysis (Ln=Eu; AG=NB, NI, Bn)\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7254638/v1/37fbdfde83a961619f1a2e15.png"},{"id":88333709,"identity":"f9eac821-d09b-4484-a9ec-b6857606cec5","added_by":"auto","created_at":"2025-08-05 11:25:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":263281,"visible":true,"origin":"","legend":"\u003cp\u003eFrontier molecular orbital and ELF, LOL diagram of the three different substrates of europium complex\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7254638/v1/f5e87a3307a8e5a55911f59b.png"},{"id":88332764,"identity":"afe2d1b6-de60-48c7-88f2-295ac6e66cf6","added_by":"auto","created_at":"2025-08-05 11:09:34","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":51739,"visible":true,"origin":"","legend":"\u003cp\u003eThe reaction channel and energy variation of ester hydrolysis under alkaline conditions of different lanthanide metal complexes (Ln=Eu, Gd, Tb; AG=Nb).\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7254638/v1/292ef423b64e0ceba8076044.png"},{"id":89235831,"identity":"d7d86d7d-f857-4de3-8adf-f05a27e93b64","added_by":"auto","created_at":"2025-08-17 15:31:44","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1031326,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7254638/v1/3979c30e-0bf8-43fc-a7f9-e68e3c3181cd.pdf"},{"id":88332772,"identity":"2e0e6b31-60c2-4d15-8127-e189b1a499e2","added_by":"auto","created_at":"2025-08-05 11:09:34","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":7372677,"visible":true,"origin":"","legend":"","description":"","filename":"Supportinginformation.doc","url":"https://assets-eu.researchsquare.com/files/rs-7254638/v1/9cd8709b4341746ca514e460.doc"},{"id":88332763,"identity":"9b0f4ecf-80d7-486e-ad9e-5ae751537f29","added_by":"auto","created_at":"2025-08-05 11:09:34","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":27191,"visible":true,"origin":"","legend":"\u003cp\u003eScheme 1. The DOTA monoesters of lanthanide complexes (Ln = Eu, Gd, Tb) hydrolyze under alkaline conditions to form the corresponding DOTA complexes.\u003c/p\u003e","description":"","filename":"Scheme1.png","url":"https://assets-eu.researchsquare.com/files/rs-7254638/v1/dd4938361633230c2c799d73.png"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eDFT study of molecular probe release process of Ln-DOTA (Eu, Gd, Tb) ester complexes\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eHepatocellular carcinoma (HCC), as the third leading cause of death from malignant tumors globally, poses a significant to human health and severely affects the quality of life and survival time of patients. The implementation of early detection of HCC, strengthening early identification, diagnosis, and intervention, is important way to improve the success rate of treatment and extend the survival time of patients[\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Magnetic resonance imaging (MRI) is a non-invasive, high-resolution imaging that has become an important tool for clinical diagnosis and has a higher sensitivity and specificity in detecting malignant and benign liver lesions [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. MRI has significant advantages in the field of medical because of its characteristics such as no ionizing radiation, high soft tissue contrast, multiple sequences, and multi-plane imaging [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Also, in order to further improve the sensitivity of conventional, some clinical MRI imaging uses contrast agents to enhance the imaging, which can provide more morphological and functional information. It not only increases the contrast between the accumulation area and the background but can also further enhance the contrast of the image by affecting the relaxation process of water protons in the surrounding tissues, thereby improving the accuracy of disease diagnosis. This molecular imaging principle of great significance for achieving accurate diagnosis and targeted treatment [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eLanthanide complexes have been shown to be a good alternative to organic fluorophores due to their long emission lifetimes and sharp emission bands, which enable elimination of biological autofluorescence and scattering light by time-control techniques [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Luminescent lanthanide complexes can also be used as ideal MRI contrast agents by tuning the parameters of the complexes to change the MRI signal intensity and the water relaxation rate. Therefore, lanthanide complexes have unique advantages for designing responsive probes to monitor the changes of bothinescence and MRI contrast in the same system [\u003cspan additionalcitationids=\"CR13 CR14 CR15\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Currently, gadolinium (III) contrast agents(CA) are considered the workhorses of this diagnostic imaging technique [\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The contrast agents of gadolinium are generally by the combination of Gd (III) with organic ligands to form stable organic complexes that can be excreted from the body after intravenous injection. It occupies special position in MRI and is widely used in clinics for the detection and diagnosis of cancer, infection, hemorrhage, and nervous system diseases, etc. In the molecular probe design of clinical application, the chelates formed by the cage-like small molecule DTPA and DOTA with multi-coordination witholinium ions are the best method at present. The connection of Gd\u003csup\u003e3+\u003c/sup\u003e with polyamino carboxylic acid ligands (including DOTA, DOTPA, DO3A, DTTA, DTPA and EDTA) has strong stability and low toxicity, and can enhance the intensity of CA in MRI signal [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn 2018, the research team of Liu and Nazare [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] designed and explored the MRI contrast agent, a nitrobenzyl -substituted gadolinium complex, G-DOTA-PNB. The probe can be activated to the Gd-DOTA in the environment of nitroreductase (NTR), which can detect NTR by enhancing the contrast performance. Recently, Foster et al. Reported [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] the synthesis of similar lanthanide complexes probe, which was extended to the europium, gadolinium and terbium elements, and the corresponding complexes with single ester formed by groups such as nitrophenyl, imidazolyl, phenyl, etc. These esters were activated under alkaline conditions to generate the corresponding DOTA complexes (Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e), and the changes of their optical and relaxation properties were tested, and the results were well studied. The experimental process of activated release was found to have added ethanol solvent, and it could be easily completed at 40℃. In order to deeply the microscopic mechanism and reaction activity of the reaction process, this paper uses the PBE1PBE method of density functional theory to calculate and study the possible structure of the reaction, explore and analyze its microscopic state of activated reaction process, reaction activity and the influence of its metal center and organic group on the change.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"2. Computational details","content":"\u003cp\u003eAll the theoretical calculations in this work were performed using the Gaussian 09 software [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. The PBE1PBE computational method [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] of the PBE0 was employed to perform the geometric configuration optimization and vibrational frequency calculations for lanthanide complexes and ligands in the gas phase and in solvent, with the DFT-D3(BJ) correction[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] applied to the systems under investigation. The PBE0 functional has been shown to provide reasonable and reliable results for lanthanide and actinide [\u003cspan additionalcitationids=\"CR30 CR31\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. For lanthanides Eu, Gd, and Tb, the 52\u0026ndash;54 core electrons of the atoms were treated with effective core pseudo potentials (RECPs) [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], using ECP52MWB-SEG, ECP53MWB-SEG, ECP54B-SEG as corresponding valence basis sets. For other light elements C, H, N, and O, the 6-311G(d,p) basis set was used. All the stationary structures were verified by vibrational frequency analysis, the intermediate has no negative eigenvalues, and the transition state structure has only one negative. To approximate the experimental environment and obtain more accurate energies, the solvent effect of the reaction was considered using the SMD solvation model [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e], ethanol was selected as solvent, and the Gibbs free energies of the solvent process were obtained at the PBE0/def2TZVP theoretical level [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. The intrinsic reaction coordinate (IRC) calculation [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] was performed to ensure that each transition state structure was connected to the corresponding two stable structures on the reaction path. The wave function analysis was performed using Multiwfn 3.8 software package[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], and the 3D figures were drawn using the Gauss View [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] and CYLview software [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e"},{"header":"3. Result and discussion","content":"\u003cp\u003eBased on the experimental research of Foster and Sneddon et al. [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] and the possible mechanism of ester hydrolysis under alkaline conditions, a potential pathway for system was proposed in this paper, combined with the reaction in Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The reaction is an S\u003csub\u003eN1\u003c/sub\u003e nucleophilic substitution reaction with a two-step process. n the first step, the nucleophile attacks the C atom in the ester. The second step of the reaction is the departure of the leaving group from the compound.\u003c/p\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Alkaline hydrolysis of the nitrobenzyl monoester of the Eu complex\u003c/h2\u003e\u003cp\u003eIn the reaction of Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, firstly, the lanthanide metal center was selected as europium, and 4-nitrobenzeneNb) was selected as the research object to undergo hydrolysis process under alkaline conditions. The specific reaction path is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, and the geometries of the various stationary points with key structural parameters are given in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. It can be seen from Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e that the intermediate Eu-1a is formed first by the attack reaction of OH\u003csup\u003e\u0026minus;\u003c/sup\u003e on the central atom Eu of substrate R. This step decreases the energy by 5.35 kcal/mol. In Eu-1a, the newly formed Eu-O\u003csup\u003e3\u003c/sup\u003e bond length is 2.229 \u0026Aring;, and the Eu-O\u003csup\u003e1\u003c/sup\u003e is completely dissociated. Subsequently, the OH nucleophile in Eu-1a attacks the C atom in the ester bond of this molecule through the transition state Eu-tsa1 to form the intermediate Eu-2a. In Eu-tsa1, the O\u003csup\u003e3\u003c/sup\u003e-C bond length is 2.310 \u0026Aring;, and the ester C atom changes from \u003cem\u003esp\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e to \u003cem\u003esp\u003c/em\u003e\u003csup\u003e\u003cem\u003e3\u003c/em\u003e\u003c/sup\u003e hybridization during the process from Eu-1a to Eu-2a. The activation free energy of this step is 3.07 kcal/mol, and the intermediate Eu-2a is 10.63 kcal/mol lower in energy than Eu-1a, and its stability is enhanced. Then, the leaving group 4-nitrobenzyloxy dissociates from the ester bond to form the carboxylic acid intermediate Eu-3a, in which the O atom of the leaving group is coordinated to the Eu center atom. In Eu-tsa2, the distance between dissociated C and O\u003csup\u003e2\u003c/sup\u003e is 1.800 \u0026Aring;, and O\u003csup\u003e2\u003c/sup\u003e is also bonded to the Eu atom with a bond length of 2.349 \u0026Aring;. The ester group carbon atom reverts to \u003cem\u003esp\u003c/em\u003e\u003csup\u003e\u003cem\u003e2\u003c/em\u003e\u003c/sup\u003e hybridization. The relative free energy from Eu-2a to Eu-tsa2 is 12.85 kcal/mol, and the free energy of Eu-3a is 5.83 kcal/mol higher than that of Eu-2a, indicating that this step is an endothermic process. The last step is the hydrogen transfer from the carboxylic acid to the benzyl alcohol through the Eu-tsa3 transition state, giving product of Eu-DOTA complex Eu-4a and p-nitrobenzyl alcohol. In Eu-4a, the carboxylic oxygen atom that transfers the lost hydrogen atom coordinates to Eu atom at the center of the complex. The activation free energy of this step is 4.9 kcal/mol, which is also a strong exothermic process, and its value is 23.40 kcal/mol. The whole reaction a relatively low activation energy, and the reaction is easily completed under the experimental condition of 40 ℃, and the overall reaction is exothermic 33.5 kcal/mol. This provides a good mechanistic complement and microscopic explanation for experimental research [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e3.2 The influence of different reactant ligands and metal centers on the activation of hydrolysis reaction\u003c/h2\u003e\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\u003ch2\u003e3.2.1 Different reactant ligands\u003c/h2\u003e\u003cp\u003eBased on the experimental research of Foster et al.[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], this paper selects different reactant ligands of 1-methyl-2-nitroimidaz(NI) and phenyl(Bn) to replace 4-nitrobenzyl(NB) for similar mechanism research under the condition of constant Eu central. The relevant coordinates of the specific stationary structures are given in the Supporting Information. The possible pathways for hydrolysis reaction of the three different reaction substrates are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e as an energy profile, where pathways a, b, c are the substituents of the substrate NB, NI, Bn, respectively. Comparison of the channels of three reactants, the trend of the energy curve is basically the same. It can be seen from Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e that the energies of the first and second transition states are lower than those of the reactants, and the three substrates are relatively close, Eu-tsa1 to Eu-tsc1 is -2.28 to 2.04 kcal/mol, and Eu-ts (a2-c2) is -4.03 to -1.57 kcal/mol. However, in the third transition state, channel b has a significantly higher energy than channels a and c, with the relationship being Eu-tsb3(5.75 kcal/mol)\u0026thinsp;\u0026gt;\u0026thinsp;Eu-tsc3(-1.98 kcal/mol)\u0026thinsp;\u0026gt;\u0026thinsp;Eu-tsa3(-5.36kcal/mol). Overall, the three reactions have low activation energies and are easily achieved under experimental conditions. Moreover, they are all strong exothermic processes, with the release of heat from 31.94 to 33.55 kcal/mol. At the same time, the frontier molecular orbitals of three reactant structures were calculated and investigated on the same theoretical level, and the specific frontier molecular orbitals (HOMO and LUMO) diagram and orbital energy level are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The energies of the frontier molecular orbitals increase in the order R-a, R-b, R-c with the values of 0.1588 0.1638, and 0.1996 eV, respectively, which is also consistent with the three activation energies of the first step of the reaction in order. The projected plots of the electronic localization function (ELF) and the localized-orbital locator (LOL) also present the charge density and charge distribution in the molecular intuitively.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\u003ch2\u003e3.2.2 The influence of metal center\u003c/h2\u003e\u003cp\u003eTo further explore the effect of different metal centers on the reactivity, subsequent systematic calculations were performed by choosing Gd and Tb to replace the Eu atom reactant R in channel a, respectively. The calculated energy barriers are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, and the Cartesian coordinates of the structures are shown in the Supporting Information. The calculated results show that the hydrolysis process of Gd and Tb metal complexes has three processes similar to Eu metal complexes, i.e. the alkaline nucleophile attacks the ester C atom, the ester bond dissociates the leaving group of alcohol, and the hydrogen transfer to obtain the DOTA complex. Moreover, the relative activation free energies of the three reactants are close to each other and also low. The first step is the rate-determining step of the whole reaction and the activation energy relationship is \u003cem\u003eG\u003c/em\u003e\u003csub\u003eTb\u003c/sub\u003e (6.48 kcal/mol)\u0026thinsp;\u0026gt;\u0026thinsp;\u003cem\u003eG\u003c/em\u003e\u003csub\u003eGd\u003c/sub\u003e (6.02 kcal/mol)\u0026thinsp;\u0026gt;\u0026thinsp;\u003cem\u003eG\u003c/em\u003e\u003csub\u003eEu\u003c/sub\u003e (3.07 kcal/mol). Since Eu, Gd, and Tb are lanthanide elements, they have similar chemical properties, and the small energy gap calculated can also predict the corresponding lanthanide complexes have similar reaction channels, and it is easy to carry out in the experiment, that is, the reaction activity of lanthanide metal center little effect on this hydrolysis reaction.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"4. Conclusion","content":"\u003cp\u003eIn this work, the process of hydrolytic release in alkaline condition of the complex molecular probe of lanthanide DOTA ester was systematically investigated by using PBE0 calculation method of DFT. According to the theoretical calculation results, the following conclusion can be drawn: (1) From the analysis of the potential energy surface and the main configurations, it is clear that the complex probe undergoes three possible steps in the hydrolytic in an alkaline environment, i.e., the nucleophile attacks the ester C atom, the ester bond dissociates the leaving group of the alcohol, the hydrogen transfer completes the release to obtain the DOTA complex. (2) Comparing the three different alcohol substituents of the reactant, the NI group has a relatively high activation energy in the final hydrogen transfer, but overall activation energies are all low, it indicates that this reaction can be easily achieved under experimental conditions. (3) Different lanthanide metal centers have little effect on the hydrolytic activity of the reaction complex. (4) This computational study can provide a very valuable complement to the experimental study of the Foster research team, and also provide an important reference for the mechanistic of the hydrolysis reaction of other lanthanide or transition metal complexes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eSupporting information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSupporting information includes the Cartesian coordinates of all structures reported in this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe sincerely thank the National Natural Science Foundation of China, the Natural Science Foundation of Gansu Province, and Lanzhou University of Arts and Sciences for their strong support. We are grateful to the reviewers for their invaluable suggestions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eXinghui Zhang: problem selection, writing, and data analysis. Haipeng Shi: simulations, result analysis, manuscript first draft. Yongning Yuan: methods, project management, result analysis, manuscript editing. Jianyi Wang: data analysis, writing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Outstanding Youth Research Program of Lanzhou University of Arts and Sciences (2021SZZX06 ), Natural Science Foundation of Gansu Province (20JR5RA479), National Natural Science Foundation of China (22165017).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e NA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e NA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e Written informed consent for publication was obtained from all participants.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e The authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTalesh GA, Tr\u0026eacute;z\u0026eacute;guet V, Merched A(2020)Hepatocellular carcinoma and statins. 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Universit\u0026eacute; de Sherbrooke: Sherbrooke, Quebec, Canada. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.cylview.org/\u003c/span\u003e\u003cspan address=\"http://www.cylview.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Schemes","content":"\u003cp\u003eScheme 1 is available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Lanthanide complexes, hydrolysis process, Ln-DOTA probe, PBE0 calculation method","lastPublishedDoi":"10.21203/rs.3.rs-7254638/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7254638/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eContext\u003c/strong\u003e Ln DOTA has been proven to have important application value in clinical medicine schools. Recently, there have been experimental reports on its probe hydrolysis release process. In order to clarify the specific micro reaction mechanism and the influencing factors of hydrolysis activity, this paper uses computational chemistry methods to systematically calculate and investigate the release reaction mechanism and hydrolytic activity of lanthanide ester complexes Ln-DOTA molecular probes under alkaline conditions. Different alcohol-based substituents NB, NI, Bn and lanthanide metal centers (Ln = Eu, Gd, Tb) were selected as reactants to complete the calculation research under the corresponding experimental conditions. The calculated results showed that this reaction includes three possible steps: the nucleophilic attack of the ester carbon atom, the dissociation of the alcohol group the ester bond, and the hydrogen transfer to the alcohol group, and finally the release process is completed to obtain the DOTA product. The activation energies are low (G \u0026lt; 5.75 kcal/mol) and the lanthanide metal center and different substituents have influence, but minor changes do not have a significant effect on the reaction mechanism and activity, indicating that it is easy to accomplish the hydrolytic release of lanthanide complexes under the existing mild experimental conditions, which is consistent with the results of experimental research. Meanwhile, the computational research also provides important basis for further exploring the mechanism of such reactions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e The geometry optimization and electronic properties calculations based on density functional theory were performed using the PBE1PBE method. All the theoretical calculations in this work were performed using the Gaussian 09 software. The lanthanide atoms Eu, Gd, and Tb are calculated using effective core pseudopotentials (RECPs) with 52–54 core electrons, while other atoms are selected from the 6-311G (d, p) basis group. Accurate free energy calculations were performed using the SMD solvent model at the PBE0/def2TZVP theoretical level.\u003c/p\u003e","manuscriptTitle":"DFT study of molecular probe release process of Ln-DOTA (Eu, Gd, Tb) ester complexes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-05 11:09:29","doi":"10.21203/rs.3.rs-7254638/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1e623e77-d287-4069-915b-46c99d0ddd55","owner":[],"postedDate":"August 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-17T15:23:38+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-05 11:09:29","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7254638","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7254638","identity":"rs-7254638","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}