{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T15:55:46Z","timestamp":1772466946193,"version":"3.50.1"},"reference-count":71,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science, Technological Development, and Innovation of the Republic of Serbia","award":["451-03-33\/2026-03\/200017"],"award-info":[{"award-number":["451-03-33\/2026-03\/200017"]}]},{"name":"bilateral Serbia-NR China project","award":["003417078 2024 013440 003 000 620 021"],"award-info":[{"award-number":["003417078 2024 013440 003 000 620 021"]}]},{"DOI":"10.13039\/501100016047","name":"Science Fund of the Republic of Serbia","doi-asserted-by":"publisher","award":["7282"],"award-info":[{"award-number":["7282"]}],"id":[{"id":"10.13039\/501100016047","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background: Bone-seeking radiopharmaceuticals based on bisphosphonates enable targeted therapy of skeletal metastases. They are suitable carriers for therapeutic radionuclides such as terbium-161 (161Tb), a \u03b2\u2212 emitter that additionally releases short-range conversion and Auger electrons, which may enhance radiation dose delivery to small lesions. This study explored the potential of the well-established DOTA conjugated bisphosphonate BPAMD (4-{[(bis(phosphonomethyl))carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10 tetraazacyclododec-1-yl)acetic acid) radiolabeled with 161Tb as a bone-targeted radiopharmaceutical, focusing on the theranostic and radiophysical advantages conferred by the radionuclide. Methods: BPAMD was radiolabeled with 161Tb and 177Lu under mild conditions (pH 4.5, 95 \u00b0C, 30 min); subsequently, the radiochemical purity was assessed by radio-TLC. Physicochemical properties (charge, lipophilicity, protein binding), in vitro stability (saline and human serum, 48 h), and hydroxyapatite (HAP) binding were evaluated for [161Tb]Tb-BPAMD. Biodistribution was investigated in healthy Wistar rats (n = 3 per time point) at 2 h, 24 h, and 7 days post-injection. Computational density functional theory (DFT) analyses were performed to explore the coordination chemistry of Tb3+ and Lu3+ with BPAMD. Results: Both complexes achieved a radiochemical yield of greater than 98%. [161Tb]Tb-BPAMD exhibited negative charge, high hydrophilicity (logP = \u22123.92 \u00b1 0.13), low protein binding (19.07 \u00b1 1.01%), excellent radiochemical stability under simulated physiological conditions (&gt;97% at 48 h), and strong hydroxyapatite affinity (&gt;98% with \u226510 mg HAP). Biodistribution showed high, stable bone uptake (8.06% ID\/g at 2 h; 6.70% ID\/g at 24 h; 5.31% ID\/g at 7 d) with rapid blood clearance (&lt;0.001% ID\/g at 24 h) and low non-target retention. To contextualize its performance, [161Tb]Tb-BPAMD was compared with [177Lu]Lu-BPAMD, which demonstrated similarly strong skeletal retention (8.74% ID\/g at 2 h; 8.08% ID\/g at 24 h; 5.25% ID\/g at 7 d) but comparatively higher non-target organ uptake. DFT calculations indicate that both Tb3+ and Lu3+ favor octa-coordinated BPAMD complexes. Conclusions: [161Tb]Tb-BPAMD exhibits excellent radiochemical and pharmacokinetic properties, with enhanced biodistribution selectivity over [177Lu]Lu-BPAMD. Combined with the radiobiological advantages of 161Tb, it represents a promising theranostic candidate for targeted therapy of bone metastases.<\/jats:p>","DOI":"10.3390\/pharmaceutics18030312","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T14:55:01Z","timestamp":1772463301000},"page":"312","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["[161Tb]Tb-BPAMD as a High-Affinity Agent for Skeletal Targeting: Radiochemical and Biodistribution Insights"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3972-313X","authenticated-orcid":false,"given":"Magdalena","family":"Radovi\u0107","sequence":"first","affiliation":[{"name":"\u201cVIN\u010cA\u201d Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11001 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4209-0640","authenticated-orcid":false,"given":"Pavle","family":"Sitarica","sequence":"additional","affiliation":[{"name":"\u201cVIN\u010cA\u201d Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11001 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7669-2865","authenticated-orcid":false,"given":"Dragana","family":"Stankovi\u0107","sequence":"additional","affiliation":[{"name":"\u201cVIN\u010cA\u201d Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11001 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3176-5554","authenticated-orcid":false,"given":"Marija","family":"Mirkovi\u0107","sequence":"additional","affiliation":[{"name":"\u201cVIN\u010cA\u201d Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11001 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3938-2790","authenticated-orcid":false,"given":"Drina","family":"Jankovi\u0107","sequence":"additional","affiliation":[{"name":"\u201cVIN\u010cA\u201d Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11001 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0110-7482","authenticated-orcid":false,"given":"Milo\u0161","family":"Mari\u0107","sequence":"additional","affiliation":[{"name":"\u201cVIN\u010cA\u201d Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11001 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8094-8464","authenticated-orcid":false,"given":"Marko","family":"Peri\u0107","sequence":"additional","affiliation":[{"name":"\u201cVIN\u010cA\u201d Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11001 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6340-2387","authenticated-orcid":false,"given":"Sanja","family":"Vranje\u0161-\u0110uri\u0107","sequence":"additional","affiliation":[{"name":"\u201cVIN\u010cA\u201d Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11001 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9352-8036","authenticated-orcid":false,"given":"Aleksandar","family":"Vukadinovi\u0107","sequence":"additional","affiliation":[{"name":"\u201cVIN\u010cA\u201d Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11001 Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e126333","DOI":"10.5812\/aapm-126333","article-title":"Multimodal Clinical Approach for Treatment of Bone Metastases in Solid Tumors","volume":"12","author":"Bianco","year":"2022","journal-title":"Anesthesiol. Pain Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1188\/09.CJON.701-710","article-title":"Bone metastases from advanced cancers: Clinical implications and treatment options","volume":"13","author":"Fitch","year":"2009","journal-title":"Clin. J. Oncol. Nurs."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1053\/j.semnuclmed.2009.10.003","article-title":"Systemic Metabolic Radiopharmaceutical Therapy in the Treatment of Metastatic Bone Pain","volume":"40","author":"Paes","year":"2010","journal-title":"Semin. Nucl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"100519","DOI":"10.1016\/j.jbo.2023.100519","article-title":"Incidence and radiotherapy treatment patterns of complicated bone metastases","volume":"44","author":"Peters","year":"2024","journal-title":"J. Bone Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5195","DOI":"10.3390\/curroncol29080411","article-title":"Treatment of Bone Metastasis","volume":"29","author":"Errani","year":"2022","journal-title":"Curr. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ouvrard, E., Kaseb, A., Poterszman, N., Porot, C., Somme, F., and Imperiale, A. (2023). Nuclear medicine imaging for bone metastases assessment: What else besides bone scintigraphy in the era of personalized medicine?. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1320574"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1159\/000337634","article-title":"Radionuclide therapy of bone metastases","volume":"7","author":"Fischer","year":"2012","journal-title":"Breast Care"},{"key":"ref_8","first-page":"1358","article-title":"Radiopharmaceutical therapy for palliation of bone pain from osseous metastases","volume":"45","author":"Batraki","year":"2004","journal-title":"J. Nucl. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.apradiso.2016.01.003","article-title":"Palliative treatment of metastatic bone pain with radiopharmaceuticals: A perspective beyond Strontium-89 and Samarium-153","volume":"110","author":"Liberal","year":"2016","journal-title":"Appl. Radiat. Isot."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0001-2998(05)80156-4","article-title":"[153Sm]EDTMP: A potential therapy for bone cancer pain","volume":"22","author":"Holmes","year":"1992","journal-title":"Semin. Nucl. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.arcmed.2014.03.006","article-title":"153Sm-EDTMP for pain relief of bone metastases from prostate and breast cancer and other malignancies","volume":"45","year":"2014","journal-title":"Arch. Med. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1016\/S0959-8049(97)00155-X","article-title":"A dose-controlled study of 153Sm- ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases","volume":"33","author":"Resche","year":"1997","journal-title":"Eur. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.nucmedbio.2009.09.004","article-title":"Multispecies animal investigation on biodistribution, pharmacokinetics and toxicity of 177Lu-EDTMP, a potential bone pain palliation agent","volume":"37","author":"Balogh","year":"2010","journal-title":"Nucl. Med. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1515\/ract-2019-3219","article-title":"Formulation of \u2018ready-to-use\u2019 human clinical doses of 177Lu-labeled bisphosphonate amide of DOTA using moderate specific activity 177Lu and its preliminary evaluation in human patient","volume":"108","author":"Chakraborty","year":"2020","journal-title":"Radiochim. Acta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/s13550-016-0161-3","article-title":"177Lu-labelled macrocyclic bisphosphonates for targeting bone metastasis in cancer treatment","volume":"6","author":"Bergmann","year":"2016","journal-title":"EJNMMI Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"K\u00e1lm\u00e1n, F.K., Kir\u00e1ly, R., and Br\u00fccher, E. (2008). Stability constants and dissociation rates of the EDTMP complexes of Samarium(III) and Yttrium(III). Eur. J. Inorg. Chem., 4719\u20134727.","DOI":"10.1002\/ejic.200800582"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/S0969-8051(97)80001-7","article-title":"The influence of EDTMP-concentration on the biodistribution of radio- lanthanides and 225-Ac in tumor-bearing mice","volume":"24","author":"Beyer","year":"1997","journal-title":"Nucl. Med. Biol."},{"key":"ref_18","first-page":"94","article-title":"Development of a [177Lu]BPAMD labeling kit and an automated synthesis module for routine bone targeted endoradiotherapy","volume":"30","author":"Meckel","year":"2015","journal-title":"Cancer Biother. Radiopharm."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1111\/cbdd.13327","article-title":"Syntheses and evaluation of 68Ga- and 153Sm-labeled DOTA-conjugated bisphosphonate ligand for potential use in detection of skeletal metastases and management of pain arising from skeletal metastases","volume":"92","author":"Chakraborty","year":"2018","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Pfannkuchen, N., Meckel, M., Bergmann, R., Bachmann, M., Bal, C., Sathekge, M., Mohnike, W., Baum, R.P., and R\u00f6sch, F. (2017). Novel radiolabeled bisphosphonates for PET diagnosis and endoradiotherapy of bone metastases. Pharmaceuticals, 10.","DOI":"10.3390\/ph10020045"},{"key":"ref_21","first-page":"67","article-title":"Convenient formulation of 68Ga-BPAMD patient dose using lyophilized BPAMD Kit and 68Ga sourced from different commercial generators for imaging of skeletal metastases","volume":"34","author":"Guleria","year":"2019","journal-title":"Cancer Biother. Radiopharm."},{"key":"ref_22","unstructured":"IAEA (2023). Pain Palliation of Bone Metastases: Production, Quality Control and Dosimetry of Radiopharmaceuticals, International Atomic Energy Agency."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1515\/ract-2015-2561","article-title":"Development and biological evaluation of 90Y-BPAMD as a novel bone seeking therapeutic Agent","volume":"104","author":"Rabiei","year":"2016","journal-title":"Radiochim. Acta"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.4103\/0973-1482.197534","article-title":"Samarium-153-(4-[((bis (phosphonomethyl)) carbamoyl) methyl]-7,10-bis (carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl) acetic acid: A novel agent for bone pain palliation therapy","volume":"12","author":"Yousefnia","year":"2016","journal-title":"J. Cancer Res. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1007\/s12149-015-1014-2","article-title":"Preparation, quality control and biodistribution assessment of 153Sm-BPAMD as a novel agent for bone pain palliation therapy","volume":"29","author":"Rabie","year":"2015","journal-title":"Ann. Nucl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1007\/s10967-016-4734-4","article-title":"Preparation and biological evaluation of 175Yb-BPAMD as a potential agent for bone pain palliation therapy","volume":"309","author":"Zolghadri","year":"2016","journal-title":"J. Radioanal. Nucl. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1007\/s10967-014-3924-1","article-title":"Preparation and biological evaluation of 166Ho-BPAMD as a potential therapeutic bone-seeking agent","volume":"304","author":"Yousefnia","year":"2015","journal-title":"J. Radioanal. Nucl. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13550-016-0171-1","article-title":"Contribution of Auger\/conversion electrons to renal side effects after radionuclide therapy: Preclinical comparison of 161Tb-folate and 177Lu-folate","volume":"6","author":"Haller","year":"2016","journal-title":"EJNMMI Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/s41181-019-0063-6","article-title":"Production and characterization of no- carrier-added $^{161}$Tb as an alternative to the therapy","volume":"4","author":"Gracheva","year":"2019","journal-title":"EJNMMI Radiopharm. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11736","DOI":"10.1021\/acs.inorgchem.0c01664","article-title":"Expanding the Scope of Pyclen-Picolinate Lanthanide Chelates to Potential Theranostic Applications","volume":"59","author":"Nizou","year":"2020","journal-title":"Inorg. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.7150\/thno.92775","article-title":"Terbium radionuclides for theranostic applications in nuclear medicine: From atom to bedside","volume":"14","author":"Koole","year":"2024","journal-title":"Theranostics"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Dur\u00e1n, M.T., Juget, F., Nedjadi, Y., Bochud, F., Grundler, P.V., Gracheva, N., M\u00fcller, C., Talip, Z., van der Meulen, N.P., and Bailat, C. (2020). Determination of 161Tb half-life by three measurement methods. Appl. Radiat. Isot., 159.","DOI":"10.1016\/j.apradiso.2020.109085"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.2967\/jnumed.124.267873","article-title":"The Emission of Internal Conversion Electrons Rather Than Auger Electrons Increased the Nucleus-Absorbed Dose for 161 Tb Compared with 177 Lu with a Higher Dose Response for [ 161 Tb]Tb-DOTA-LM3 Than for [ 161 Tb]Tb-DOTATATE","volume":"65","author":"Spoormans","year":"2024","journal-title":"J. Nucl. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/s40658-020-00301-2","article-title":"Radiation doses from 161Tb and 177Lu in single tumour cells and micrometastases","volume":"7","author":"Ferreira","year":"2020","journal-title":"EJNMMI Phys."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s41181-019-0075-2","article-title":"Auger electrons for cancer therapy\u2014A review","volume":"4","author":"Ku","year":"2019","journal-title":"EJNMMI Radiopharm. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"759","DOI":"10.2967\/jnumed.115.170423","article-title":"Dose deposits from90Y,177Lu,111In, and161Tb in micrometastases of various sizes: Implications for radiopharmaceutical therapy","volume":"57","author":"Hindie","year":"2016","journal-title":"J. Nucl. Med."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Bernhardt, P., Svensson, J., Hemmingsson, J., van der Meulen, N.P., Zeevaart, J.R., Konijnenberg, M.W., M\u00fcller, C., and Kindblom, J. (2021). Dosimetric analysis of the short-ranged particle emitter161 tb for radionuclide therapy of metastatic prostate cancer. Cancers, 13.","DOI":"10.3390\/cancers13092011"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"292","DOI":"10.7150\/thno.22217","article-title":"Dosimetric evaluation of radionuclides for VCAM-1- targeted radionuclide therapy of early brain metastases","volume":"8","author":"Falzone","year":"2018","journal-title":"Theranostics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.7150\/thno.15132","article-title":"Comparison between three promising \u03b2-emitting radionuclides, 67Cu, 47Sc and 161Tb, with emphasis on doses delivered to minimal residual disease","volume":"6","author":"Champion","year":"2016","journal-title":"Theranostics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1007\/s00259-013-2563-z","article-title":"Direct in vitro and in vivo comparison of 161Tb and 177Lu using a tumour-targeting folate conjugate","volume":"41","author":"Reber","year":"2014","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1186\/s40658-024-00682-8","article-title":"Quantitative SPECT imaging of 155Tb and 161Tb for preclinical theranostic radiopharmaceutical development","volume":"11","author":"Koniar","year":"2024","journal-title":"EJNMMI Phys."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.2967\/jnumed.120.258376","article-title":"First-in-human application of terbium-161: A feasibility study using 161Tb-DOTATOC","volume":"62","author":"Baum","year":"2021","journal-title":"J. Nucl. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1007\/s00259-019-04345-0","article-title":"Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer","volume":"46","author":"Umbricht","year":"2019","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.2967\/jnumed.112.107540","article-title":"A unique matched quadruplet of terbium radioisotopes for PET and SPECT and for \u03b1- and \u03b2--radionuclide therapy: An in vivo proof-of-concept study with a new receptor-targeted folate derivative","volume":"53","author":"Zhernosekov","year":"2012","journal-title":"J. Nucl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1007\/s00259-021-05564-0","article-title":"Combination of terbium-161 with somatostatin receptor antagonists\u2014A potential paradigm shift for the treatment of neuroendocrine neoplasms","volume":"49","author":"Borgna","year":"2022","journal-title":"Eur. J. Nucl. Med. Mol. Imaging"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1007\/BF01254561","article-title":"Evaluation in vitro and in rats of161Tb-DTPA-octreotide, a somatostatin analogue with potential for intraoperative scanning and radiotherapy","volume":"22","author":"Breeman","year":"1995","journal-title":"Eur. J. Nucl. Med."},{"key":"ref_47","first-page":"27","article-title":"Investigation of 177Lu-labeled HEDP, DPD, and IDP as potential bone pain palliation agents","volume":"13","year":"2020","journal-title":"J. Radiat. Res. Appl. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1002\/aoc.2870","article-title":"Novel tetradentate diamine dioxime ligands: Synthesis, characterization and in vivo behavior of their 99mTc-complexes","volume":"26","author":"Mijin","year":"2012","journal-title":"Appl. Organomet. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1007\/s10967-015-4225-z","article-title":"Preparation and biological assessment of 177Lu-BPAMD as a high potential agent for bone pain palliation therapy: Comparison with 177Lu-EDTMP","volume":"307","author":"Yousefnia","year":"2016","journal-title":"J. Radioanal. Nucl. Chem."},{"key":"ref_50","unstructured":"European Parliament (2010). Directive 2010\/63\/EU of the European Parliament and of the Council of 22 September 2010 on the Protection of Animals Used for Scientific Purposes, European Union, EUR-Lex. Available online: https:\/\/eur-lex.europa.eu\/eli\/dir\/2010\/63\/oj\/eng."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3098","DOI":"10.1103\/PhysRevA.38.3098","article-title":"Density-functional exchange-energy approximation with correct asymptotic behavior","volume":"38","author":"Becke","year":"1988","journal-title":"Phys. Rev. A"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1039\/b515623h","article-title":"Accurate Coulomb-fitting basis sets for H to Rn","volume":"8","author":"Weigend","year":"2006","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2229","DOI":"10.1021\/ct900090f","article-title":"All-electron scalar relativistic basis sets for the lanthanides","volume":"5","author":"Pantazis","year":"2009","journal-title":"J. Chem. Theory Comput."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1021\/ct800047t","article-title":"All-electron scalar relativistic basis sets for third-row transition metal atoms","volume":"4","author":"Pantazis","year":"2008","journal-title":"J. Chem. Theory Comput."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1007\/s00214-012-1292-x","article-title":"All-electron scalar relativistic basis sets for the 6p elements","volume":"131","author":"Pantazis","year":"2012","journal-title":"Theor. Chem. Acc."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1021\/ct100736b","article-title":"All-Electron Scalar Relativistic Basis Sets for the Actinides","volume":"7","author":"Pantazis","year":"2011","journal-title":"J. Chem. Theory Comput."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e70019","DOI":"10.1002\/wcms.70019","article-title":"Software Update: The ORCA Program System\u2014Version 6.0","volume":"15","author":"Neese","year":"2025","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1002\/jcc.26942","article-title":"The SHARK integral generation and digestion system","volume":"44","author":"Neese","year":"2023","journal-title":"J. Comput. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1740","DOI":"10.1002\/jcc.10318","article-title":"An Improvement of the Resolution of the Identity Approximation for the Formation of the Coulomb Matrix","volume":"24","author":"Neese","year":"2003","journal-title":"J. Comput. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1016\/j.jpcs.2003.11.015","article-title":"Definition of corresponding orbitals and the diradical character in broken symmetry DFT calculations on spin coupled systems","volume":"65","author":"Neese","year":"2004","journal-title":"J. Phys. Chem. Solids"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"164104","DOI":"10.1063\/5.0040798","article-title":"A trust-region augmented Hessian implementation for restricted and unrestricted Hartree-Fock and Kohn-Sham methods","volume":"154","year":"2021","journal-title":"J. Chem. Phys."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1002\/jlcr.4128","article-title":"Towards Optimal Automated 68Ga-Radiolabeling Conditions of the DOTA-Bisphosphonate BPAMD Without Pre-Purification of the Generator Eluate","volume":"67","author":"Souche","year":"2024","journal-title":"J. Label. Compd. Radiopharm."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/j.nucmedbio.2012.04.007","article-title":"68Ga-BPAMD: PET-imaging of bone metastases with a generator based positron emitter","volume":"39","author":"Fellner","year":"2012","journal-title":"Nucl. Med. Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.nucmedbio.2016.07.009","article-title":"A DOTA based bisphosphonate with an albumin binding moiety for delayed body clearance for bone targeting","volume":"43","author":"Meckel","year":"2016","journal-title":"Nucl. Med. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.ejps.2018.08.008","article-title":"An examination of protein binding and protein-facilitated uptake relating to in vitro-in vivo extrapolation","volume":"123","author":"Bowman","year":"2018","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2953","DOI":"10.1002\/jps.23614","article-title":"Plasma protein binding: From discovery to development","volume":"102","author":"Bohnert","year":"2013","journal-title":"J. Pharm. Sci."},{"key":"ref_67","first-page":"6","article-title":"Radiolanthanide complexes with tetraazamacrocycles bearing methylphosphonate pendant arms as bone seeking agents","volume":"51","author":"Gano","year":"2007","journal-title":"Q. J. Nucl. Med. Mol. Imaging"},{"key":"ref_68","first-page":"1","article-title":"Biocomplexes in radiochemistry","volume":"1","author":"Ogawa","year":"2019","journal-title":"Phys. Sci. Rev."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1021\/ml5004603","article-title":"Structural requirements for bisphosphonate binding on hydroxyapatite: NMR study of bisphosphonate partial esters","volume":"6","author":"Puljula","year":"2015","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/j.bone.2005.05.003","article-title":"Novel insights into actions of bisphosphonates on bone: Differences in interactions with hydroxyapatite","volume":"38","author":"Nancollas","year":"2006","journal-title":"Bone"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Souche, C., Fouillet, J., Rubira, L., Donz\u00e9, C., Deshayes, E., and Fersing, C. (2024). Bisphosphonates as Radiopharmaceuticals: Spotlight on the Development and Clinical Use of DOTAZOL in Diagnostics and Palliative Radionuclide Therapy. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010462"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/3\/312\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T15:02:34Z","timestamp":1772463754000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/18\/3\/312"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,28]]},"references-count":71,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["pharmaceutics18030312"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics18030312","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,28]]}}}