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Previously, we developed [67Ga]Ga-NOTA-KV6, an SVS-1 derivative for tumor imaging, which demonstrated favorable early tumor uptake but poor retention. To address this limitation, we designed and evaluated a novel d-amino acid\u2013based SVS-1 analogue, [67Ga]Ga-NOTA-d-KV6, to enhance metabolic stability and improve pharmacokinetic properties. Fluorescein isothiocyanate (FITC)-labeled d-KV6 exhibited high accumulation in cancer cells, similar to that of FITC-KV6. In addition, uptake of [67Ga]Ga-NOTA-d-KV6 was significantly greater in cancer cells than in normal cells. Similar to [67Ga]Ga-NOTA-KV6, cellular uptake of [67Ga]Ga-NOTA-d-KV6 in cancer cells was significantly reduced at low temperature (4 \u00b0C) and in the presence of several different types of endocytic inhibitors, indicating internalization via multiple endocytosis pathways. Metabolic stability studies revealed that [67Ga]Ga-NOTA-d-KV6 was significantly more stable than [67Ga]Ga-NOTA-KV6. An in vivo biodistribution study of [67Ga]Ga-NOTA-d-KV6 revealed low blood retention, high accumulation in the liver and kidneys, and minimal uptake by other organs. Tumor accumulation of [67Ga]Ga-NOTA-d-KV6 was moderate, but tumor retention was improved compared with that of [67Ga]Ga-NOTA-KV6, leading to a tumor-to-blood ratio of 17.3 at 240 min postinjection. These findings demonstrate that d-amino acid substitution improved the plasma stability and tumor retention of the CAP derivative while maintaining preferential uptake in cancer cells. Although further optimization is required to reduce liver and kidney accumulation and improve tumor-to-background contrast, mirror peptide formation represents a promising strategy for the development of CAP-based cancer theranostic agents.<\/jats:p>","DOI":"10.1021\/acsomega.6c05291","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T09:56:51Z","timestamp":1788429411000},"page":"54234-54244","source":"Crossref","is-referenced-by-count":0,"title":["Synthesis and Fundamental\nEvaluation of [67Ga]Ga-NOTA-\n                    <scp>D<\/scp>\n                    -KV6\nas a Potential Cationic Amphiphilic\nPeptide Probe for Tumor Imaging"],"prefix":"10.1021","volume":"11","author":[{"given":"Takeshi","family":"Chiga","sequence":"first","affiliation":[{"name":"Kanazawa University , , Kakuma-machi , , ,","place":["Kanazawa, Ishikawa, Japan, 920-1192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8141-1212","authenticated-orcid":true,"given":"Takeshi","family":"Fuchigami","sequence":"additional","affiliation":[{"name":"Kanazawa University , , Kakuma-machi , , ,","place":["Kanazawa, Ishikawa, Japan, 920-1192"]},{"name":"Kanazawa University , , Takara-machi 13-1 , , ,","place":["Kanazawa, Ishikawa, Japan, 920-8641"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akari","family":"Matsuura","sequence":"additional","affiliation":[{"name":"Kyoto University , , Kyoto daigaku-Katsura C3, Nishikyo-ku , ,","place":["Kyoto, Japan, 615-8540"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3405-4512","authenticated-orcid":true,"given":"Masayuki","family":"Munekane","sequence":"additional","affiliation":[{"name":"Kanazawa University , , Kakuma-machi , , ,","place":["Kanazawa, Ishikawa, Japan, 920-1192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5071-7574","authenticated-orcid":true,"given":"Kenji","family":"Mishiro","sequence":"additional","affiliation":[{"name":"Kanazawa University , , Kakuma-machi , , ,","place":["Kanazawa, Ishikawa, Japan, 920-1192"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sakura","family":"Yoshida","sequence":"additional","affiliation":[{"name":"Nagasaki University , , 1-14 Bunkyo-machi , ,","place":["Nagasaki, Japan, 852-8521"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3691-3608","authenticated-orcid":true,"given":"Makoto","family":"Oba","sequence":"additional","affiliation":[{"name":"The University of Kitakyushu , , , ,","place":["Kitakyushu, Fukuoka, Japan, 808-0135"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Wakabayashi","sequence":"additional","affiliation":[{"name":"Kyoto Prefectural University of Medicine , , ,","place":["Kyoto, Japan, 606-0823"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seigo","family":"Kinuya","sequence":"additional","affiliation":[{"name":"Kyoto Prefectural University of Medicine , , ,","place":["Kyoto, Japan, 606-0823"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1691-7302","authenticated-orcid":true,"given":"Kazuma","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Kanazawa University , , Kakuma-machi , , ,","place":["Kanazawa, Ishikawa, Japan, 920-1192"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"2026091510101401100_cit1","doi-asserted-by":"publisher","first-page":"294","DOI":"10.3389\/fmicb.2013.00294","article-title":"From antimicrobial to anticancer\npeptides. 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