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Previously, we developed a fibroblast activation protein inhibitor (FAPI)-based covalent targeted radioligand (CTR) for improved detection sensitivity and accuracy. In this first-in-class clinical trial, we head-to-head compared [68Ga]Ga-CTR-FAPI PET-CT and [18F]fluorodeoxyglucose ([18F]FDG) PET-CT in 50 patients with MTC. The primary endpoint was the patient-based detection rate, with [68Ga]Ga-CTR-FAPI exhibiting higher detection than [18F]FDG (98% vs. 66%, P = 0.0002). This improved detection was attributed to increased tumor uptake (maximum standardized uptake value = 11.71 \u00b1 9.16 vs. 2.55 \u00b1 1.73, P &amp;lt; 0.0001). Diagnostic accuracy, validated on lesions with gold-standard pathology, was greater for [68Ga]Ga-CTR-FAPI compared with [18F]FDG (96.7% vs. 43.3%, P &amp;lt; 0.0001). Notably, the management of 32% of patients was altered following [68Ga]Ga-CTR-FAPI PET-CT, and the surgical plan was changed for 66.7% of patients. Overall, [68Ga]Ga-CTR-FAPI PET-CT provided superior detection and diagnostic accuracy compared with [18F]FDG PET-CT, enabling precision management of patients with MTC.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>In this first-in-class clinical trial of CTR, [68Ga]Ga-CTR-FAPI demonstrated an improved patient-based detection rate (98%), tumor uptake (maximum standardized uptake value = 11.71 \u00b1 9.16), and pathology-validated diagnostic accuracy (96.7%) compared with the currently approved method in MTC treatment. It directly altered management in 32% of patients, enabling precision diagnosis and management of MTC.<\/jats:p>\n                    <jats:p>See related commentary by Witney, p. 264<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-24-0897","type":"journal-article","created":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T08:28:57Z","timestamp":1730190537000},"page":"316-328","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["CTR-FAPI PET Enables Precision Management of Medullary Thyroid Carcinoma"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6588-4757","authenticated-orcid":false,"given":"Ziren","family":"Kong","sequence":"first","affiliation":[{"name":"1Department of Head and Neck Surgery, National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 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