Synthesis and Preclinical Evaluation of a Novel Fluorine-18-Labeled Tracer for Positron Emission Tomography Imaging of Bruton’s Tyrosine Kinase
Bruton’s tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases. To aid in the discovery and development of BTK inhibitors and improve clinical diagnoses, we have developed a positron emission tomography (PET) radiotracer based on a selective BTK inhibitor, remibr...
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| Veröffentlicht in: | ACS pharmacology & translational science 2023-03, Vol.6 (3), p.410-421 |
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| creator | Li, Kaixuan Wang, Mingqian Akoglu, Melike Pollard, Alyssa C. Klecker, John B. Alfonso, Patricia Corrionero, Ana Prendiville, Niall Qu, Wenchao Parker, Matthew F. L. Turkman, Nashaat Cohen, Jules A. Tonge, Peter J. |
| description | Bruton’s tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases. To aid in the discovery and development of BTK inhibitors and improve clinical diagnoses, we have developed a positron emission tomography (PET) radiotracer based on a selective BTK inhibitor, remibrutinib. [18F]PTBTK3 is an aromatic, 18F-labeled tracer that was synthesized in 3 steps with a 14.8 ± 2.4% decay-corrected radiochemical yield and ≥99% radiochemical purity. The cellular uptake of [18F]PTBTK3 was blocked up to 97% in JeKo-1 cells using remibrutinib or non-radioactive PTBTK3. [18F]PTBTK3 exhibited renal and hepatobiliary clearance in NOD SCID (non-obese diabetic/severe combined immunodeficiency) mice, and the tumor uptake of [18F]PTBTK3 in BTK-positive JeKo-1 xenografts (1.23 ± 0.30% ID/cc) was significantly greater at 60 min post injection compared to the tumor uptake in BTK-negative U87MG xenografts (0.41 ± 0.11% ID/cc). In the JeKo-1 xenografts, tumor uptake was blocked up to 62% by remibrutinib, indicating the BTK-dependent uptake of [18F]PTBTK3 in tumors. |
| doi_str_mv | 10.1021/acsptsci.2c00215 |
| format | Article |
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L. ; Turkman, Nashaat ; Cohen, Jules A. ; Tonge, Peter J.</creator><creatorcontrib>Li, Kaixuan ; Wang, Mingqian ; Akoglu, Melike ; Pollard, Alyssa C. ; Klecker, John B. ; Alfonso, Patricia ; Corrionero, Ana ; Prendiville, Niall ; Qu, Wenchao ; Parker, Matthew F. L. ; Turkman, Nashaat ; Cohen, Jules A. ; Tonge, Peter J.</creatorcontrib><description>Bruton’s tyrosine kinase (BTK) is a target for treating B-cell malignancies and autoimmune diseases. To aid in the discovery and development of BTK inhibitors and improve clinical diagnoses, we have developed a positron emission tomography (PET) radiotracer based on a selective BTK inhibitor, remibrutinib. [18F]PTBTK3 is an aromatic, 18F-labeled tracer that was synthesized in 3 steps with a 14.8 ± 2.4% decay-corrected radiochemical yield and ≥99% radiochemical purity. The cellular uptake of [18F]PTBTK3 was blocked up to 97% in JeKo-1 cells using remibrutinib or non-radioactive PTBTK3. [18F]PTBTK3 exhibited renal and hepatobiliary clearance in NOD SCID (non-obese diabetic/severe combined immunodeficiency) mice, and the tumor uptake of [18F]PTBTK3 in BTK-positive JeKo-1 xenografts (1.23 ± 0.30% ID/cc) was significantly greater at 60 min post injection compared to the tumor uptake in BTK-negative U87MG xenografts (0.41 ± 0.11% ID/cc). In the JeKo-1 xenografts, tumor uptake was blocked up to 62% by remibrutinib, indicating the BTK-dependent uptake of [18F]PTBTK3 in tumors.</description><identifier>ISSN: 2575-9108</identifier><identifier>EISSN: 2575-9108</identifier><identifier>DOI: 10.1021/acsptsci.2c00215</identifier><identifier>PMID: 36926452</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><ispartof>ACS pharmacology & translational science, 2023-03, Vol.6 (3), p.410-421</ispartof><rights>2023 American Chemical Society</rights><rights>2023 American Chemical Society.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a378t-ac0c8a9bdf75b0c74e107734d0070abb7fc0d328564c18c3ef33032a2fc86e093</citedby><cites>FETCH-LOGICAL-a378t-ac0c8a9bdf75b0c74e107734d0070abb7fc0d328564c18c3ef33032a2fc86e093</cites><orcidid>0000-0003-3107-7281 ; 0000-0003-1606-3471</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acsptsci.2c00215$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acsptsci.2c00215$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36926452$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Kaixuan</creatorcontrib><creatorcontrib>Wang, Mingqian</creatorcontrib><creatorcontrib>Akoglu, Melike</creatorcontrib><creatorcontrib>Pollard, Alyssa C.</creatorcontrib><creatorcontrib>Klecker, John B.</creatorcontrib><creatorcontrib>Alfonso, Patricia</creatorcontrib><creatorcontrib>Corrionero, Ana</creatorcontrib><creatorcontrib>Prendiville, Niall</creatorcontrib><creatorcontrib>Qu, Wenchao</creatorcontrib><creatorcontrib>Parker, Matthew F. 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The cellular uptake of [18F]PTBTK3 was blocked up to 97% in JeKo-1 cells using remibrutinib or non-radioactive PTBTK3. [18F]PTBTK3 exhibited renal and hepatobiliary clearance in NOD SCID (non-obese diabetic/severe combined immunodeficiency) mice, and the tumor uptake of [18F]PTBTK3 in BTK-positive JeKo-1 xenografts (1.23 ± 0.30% ID/cc) was significantly greater at 60 min post injection compared to the tumor uptake in BTK-negative U87MG xenografts (0.41 ± 0.11% ID/cc). 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| title | Synthesis and Preclinical Evaluation of a Novel Fluorine-18-Labeled Tracer for Positron Emission Tomography Imaging of Bruton’s Tyrosine Kinase |
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