{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:43:13Z","timestamp":1790613793714,"version":"4.1.0"},"reference-count":40,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA269349"],"award-info":[{"award-number":["R01CA269349"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010900","name":"Yale Cancer Center","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100010900","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Purpose: High tumor-associated macrophage (TAM) abundance is associated with poorer prognoses across many cancers, including renal cell carcinoma (RCC). CD68 is an established clinical biomarker for macrophages in patient tissues and is also expressed in mouse macrophages, making it an attractive target for bridging preclinical and clinical imaging of macrophages. We developed an anti-mouse CD68 (mCD68) immunoSPECT imaging agent to noninvasively quantify TAM burden in vivo and evaluate response to macrophage-modulating treatment in a syngeneic RCC tumor model. Methods: [111In]In-CHX-A\u2033-DTPA-\u03b1CD68 was synthesized by optimizing chelator conjugation and radiolabeling conditions, then characterized for binding affinity, stability, and specificity by in vitro assays. In vivo specificity was assessed in the Renca syngeneic RCC model by comparing biodistribution of [111In]In-CHX-A\u2033-DTPA-\u03b1CD68 with that of the radiolabeled IgG isotype control. ImmunoSPECT signal was correlated with ex vivo CD68 expression measured by flow cytometry of dissociated tumors and spleens. To evaluate response to macrophage-modulating treatment, a 2 \u00d7 2 factorial study was conducted in which Renca-allografted mice received either anti-CSF1R or IgG control, followed by immunoSPECT imaging with [111In]In-CHX-A\u2033-DTPA-\u03b1CD68 or radiolabeled isotype control; organ-to-heart SUVR was correlated with ex vivo CD68 expression by flow cytometry. Results: [111In]In-CHX-A\u2033-DTPA-\u03b1CD68 bound specifically to CD68 in bone marrow-derived macrophages, with high binding affinity (KD = 7.99 \u00b1 2.26 nM) to the CD68 protein. In Renca-allografted mice, immunoSPECT signal correlated strongly with ex vivo CD68 expression measured by flow cytometry of dissociated tumor and spleen cells (r = 0.854). Biodistribution studies confirmed specific uptake in vivo, with 2-fold, 8-fold, and 8-fold greater uptake in tumor, spleen, and bone marrow, respectively, compared with the radiolabeled isotype control. Treatment with the macrophage-depleting anti-CSF1R resulted in \u223c40% lower tumor-to-heart SUVR with [111In]In-CHX-A\u2033-DTPA-\u03b1CD68 compared with the isotype control, despite no change in tumor volumes. ImmunoSPECT signal remained strongly correlated with ex vivo CD68 expression measured by flow cytometry (r = 0.952). Conclusions: This study demonstrates the first example of immunoSPECT imaging of CD68 in vivo. ImmunoSPECT imaging of CD68 provides a direct, noninvasive measure of total TAM burden in RCC and represents a translatable approach for monitoring response to macrophage-modulating treatments in preclinical studies.<\/jats:p>","DOI":"10.1021\/acs.molpharmaceut.5c01902","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T20:30:23Z","timestamp":1783024223000},"page":"4079-4088","source":"Crossref","is-referenced-by-count":1,"title":["Development of [111In]In-CHX-A\u2033-DTPA-\u03b1CD68\nfor ImmunoSPECT to Image Murine Macrophages"],"prefix":"10.1021","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5211-4411","authenticated-orcid":true,"given":"Anna E.","family":"Strong","sequence":"first","affiliation":[{"name":"University of Alabama at Birmingham , , , ,","place":["Birmingham, Alabama, United States, 35233"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Belitzky","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06520"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayla","family":"Vaughn Embs","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham , , , ,","place":["Birmingham, Alabama, United States, 35233"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Katz","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06520"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Cavaliere","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06520"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dijana","family":"Djureinovic","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06520"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Borna","family":"Roohani","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham , , , ,","place":["Birmingham, Alabama, United States, 35233"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Liu","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06520"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Rothlin","sequence":"additional","affiliation":[{"name":"University of Minnesota , , , ,","place":["Minneapolis, Minnesota, United States, 55455"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianmei W.","family":"Leavenworth","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham , , , ,","place":["Birmingham, Alabama, United States, 35233"]},{"name":"University of Alabama at Birmingham , , , ,","place":["Birmingham, Alabama, United States, 35233"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Jilaveanu","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06520"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harriet M.","family":"Kluger","sequence":"additional","affiliation":[{"name":"Yale University , , , ,","place":["New Haven, Connecticut, United States, 06520"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9024-0750","authenticated-orcid":true,"given":"Bernadette","family":"Marquez-Nostra","sequence":"additional","affiliation":[{"name":"University of Alabama at Birmingham , , , ,","place":["Birmingham, Alabama, United States, 35233"]},{"name":"University of Alabama at Birmingham , , , ,","place":["Birmingham, Alabama, United States, 35233"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"2026080309073881600_cit1","doi-asserted-by":"publisher","first-page":"1080310","DOI":"10.3389\/fimmu.2023.1080310","article-title":"Macrophage: Key player in the pathogenesis\nof autoimmune diseases","volume":"14","author":"Yang","year":"2023","journal-title":"Front. 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Nucl. Med."},{"issue":"52","key":"2026080309073881600_cit24","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2409668121","article-title":"Imaging of tumor-associated\nmacrophage dynamics during immunotherapy using a CD163-specific nanobody-based\nimmunotracer","volume":"121","author":"Lauwers","year":"2024","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"issue":"9","key":"2026080309073881600_cit25","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.1007\/s00259-015-3084-8","article-title":"111In-anti-F4\/80-A3\u20131\nantibody: a novel tracer\nto image macrophages","volume":"42","author":"Terry","year":"2015","journal-title":"Eur. J. Nucl. Med. 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Cardiol."},{"issue":"1512","key":"2026080309073881600_cit29","doi-asserted-by":"publisher","first-page":"01512","DOI":"10.3389\/fonc.2019.01512","article-title":"Evaluating the Polarization of Tumor-Associated Macrophages\nInto M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and\nChallenges in Routine Clinical Practice","volume":"9","author":"Jayasingam","year":"2020","journal-title":"Front.\nOncol"},{"issue":"3","key":"2026080309073881600_cit30","doi-asserted-by":"publisher","DOI":"10.4161\/onci.23562","article-title":"Tumor-associated macrophages\nsubvert T-cell function and correlate\nwith reduced survival in clear cell renal cell carcinoma","volume":"2","author":"Dannenmann","year":"2013","journal-title":"OncoImmunology"},{"issue":"3","key":"2026080309073881600_cit31","doi-asserted-by":"publisher","first-page":"100745","DOI":"10.1016\/j.tranon.2020.100745","article-title":"Choosing The Right Animal\nModel for Renal Cancer Research","volume":"13","author":"Sobczuk","year":"2020","journal-title":"Transl. 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Immunotherapy Cancer"},{"issue":"1","key":"2026080309073881600_cit34","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1111\/cas.13842","article-title":"Combination immunotherapy\nwith interleukin-2 surface-modified tumor\ncell vaccine and programmed death receptor-1 blockade against renal\ncell carcinoma","volume":"110","author":"Zhang","year":"2019","journal-title":"Cancer Sci."},{"issue":"5","key":"2026080309073881600_cit35","doi-asserted-by":"publisher","first-page":"807","DOI":"10.2967\/jnumed.112.111781","article-title":"SPECT Imaging of Joint\nInflammation with Nanobodies Targeting the\nMacrophage Mannose Receptor in a Mouse Model for Rheumatoid Arthritis","volume":"54","author":"Put","year":"2013","journal-title":"J. Nucl. 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Drug Deliv."},{"issue":"7","key":"2026080309073881600_cit40","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.70256","article-title":"Macrophage Signaling Pathways in Health and\nDisease: From Bench to Bedside Applications","volume":"6","author":"Chi","year":"2025","journal-title":"MedComm"}],"container-title":["Molecular Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.molpharmaceut.5c01902","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article-pdf\/23\/8\/4079\/65443755\/acs.molpharmaceut.5c01902.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article-pdf\/23\/8\/4079\/65443755\/acs.molpharmaceut.5c01902.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T13:19:23Z","timestamp":1785763163000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/mpohbp\/article\/23\/8\/4079\/5180179\/Development-of-111In-In-CHX-A-DTPA-CD68-for"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,2]]},"references-count":40,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,7,2]]},"published-print":{"date-parts":[[2026,8,3]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.molpharmaceut.5c01902","relation":{},"ISSN":["1543-8384","1543-8392"],"issn-type":[{"value":"1543-8384","type":"print"},{"value":"1543-8392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,2]]}}}