Ga-68-Trivehexin

{{Short description|Contrast agent for cancer imaging}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Use dmy dates|date=January 2025}} {{Infobox drug | drug_name = | INN = | type = <!-- empty --> | image = 68Ga-Trivehexin.svg | width = 300px | alt = | caption = | image2 = | width2 = | alt2 = | caption2 = | imageL = | widthL = | altL = | imageR = | widthR = | altR = | captionLR =

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<!-- Identifiers --> | CAS_number = 3061847-76-2 | CAS_supplemental = | PubChem = 168429490 | PubChemSubstance = | IUPHAR_ligand = | DrugBank = | ChemSpiderID = | UNII = 56VJ6PVP37 | KEGG = | ChEBI = | ChEMBL = | NIAID_ChemDB = | PDB_ligand = | synonyms =

<!-- Chemical and physical data --> | IUPAC_name = <nowiki>[4,7-bis[[[3-[3-[4-[3-[4-[(3S,6S,9S,12S,18S,21S,24S,27R)-18-(3-carbamimidamidopropyl)-12-(carboxymethyl)-3,21-bis[(4-hydroxyphenyl)methyl]-6,25-dimethyl-9-(2-methylpropyl)-2,5,8,11,14,17,20,23,26-nonaoxo-1,4,7,10,13,16,19,22,25-nonazabicyclo[25.3.0]triacontan-24-yl]butylamino]-3-oxopropyl]triazol-1-yl]propylamino]-3-oxopropyl]-oxidophosphoryl]methyl]-1,4,7-triazonan-1-yl]methyl-[3-[3-[4-[3-[4-[(3S,6S,9S,12S,18S,21S,24S,27R)-18-(3-carbamimidamidopropyl)-12-(carboxymethyl)-3,21-bis[(4-hydroxyphenyl)methyl]-6,25-dimethyl-9-(2-methylpropyl)-2,5,8,11,14,17,20,23,26-nonaoxo-1,4,7,10,13,16,19,22,25-nonazabicyclo[25.3.0]triacontan-24-yl]butylamino]-3-oxopropyl]triazol-1-yl]propylamino]-3-oxopropyl]phosphinate;gallium-68(3+)</nowiki> | C=195 | H=288 | Ga=1 | N=54 | O=51 | P=3 | molecular_weight = | SMILES = C[C@H]1C(=O)N[C@H](C(=O)N2CCC[C@@H]2C(=O)N([C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)N[C@H](C(=O)N1)CC(C)C)CC(=O)O)CCCNC(=N)N)CC3=CC=C(C=C3)O)CCCCNC(=O)CCC4=CN(N=N4)CCCNC(=O)CCP(=O)(CN5CCN(CCN(CC5)CP(=O)(CCC(=O)NCCCN6C=C(N=N6)CCC(=O)NCCCC[C@H]7C(=O)N[C@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N8CCC[C@@H]8C(=O)N7C)CC9=CC=C(C=C9)O)C)CC(C)C)CC(=O)O)CCCNC(=N)N)CC1=CC=C(C=C1)O)[O-])CP(=O)(CCC(=O)NCCCN1C=C(N=N1)CCC(=O)NCCCC[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@H](C(=O)N2CCC[C@@H]2C(=O)N1C)CC1=CC=C(C=C1)O)C)CC(C)C)CC(=O)O)CCCNC(=N)N)CC1=CC=C(C=C1)O)[O-])[O-])C)CC1=CC=C(C=C1)O.[68Ga+3] | Jmol = | StdInChI = InChI=1S/C195H291N54O51P3.Ga/c1-115(2)94-139-175(277)214-118(7)169(271)229-148(100-124-43-58-133(253)59-44-124)187(289)247-82-22-34-154(247)190(292)238(10)151(184(286)226-142(97-121-37-52-130(250)53-38-121)178(280)220-136(28-19-73-208-193(196)197)172(274)211-106-163(262)217-145(103-166(265)266)181(283)223-139)31-13-16-70-202-157(256)64-49-127-109-244(235-232-127)79-25-76-205-160(259)67-91-301(295,296)112-241-85-87-242(113-302(297,298)92-68-161(260)206-77-26-80-245-110-128(233-236-245)50-65-158(257)203-71-17-14-32-152-185(287)227-143(98-122-39-54-131(251)55-40-122)179(281)221-137(29-20-74-209-194(198)199)173(275)212-107-164(263)218-146(104-167(267)268)182(284)224-140(95-116(3)4)176(278)215-119(8)170(272)230-149(101-125-45-60-134(254)61-46-125)188(290)248-83-23-35-155(248)191(293)239(152)11)89-90-243(88-86-241)114-303(299,300)93-69-162(261)207-78-27-81-246-111-129(234-237-246)51-66-159(258)204-72-18-15-33-153-186(288)228-144(99-123-41-56-132(252)57-42-123)180(282)222-138(30-21-75-210-195(200)201)174(276)213-108-165(264)219-147(105-168(269)270)183(285)225-141(96-117(5)6)177(279)216-120(9)171(273)231-150(102-126-47-62-135(255)63-48-126)189(291)249-84-24-36-156(249)192(294)240(153)12;/h37-48,52-63,109-111,115-120,136-156,250-255H,13-36,49-51,64-108,112-114H2,1-12H3,(H,202,256)(H,203,257)(H,204,258)(H,205,259)(H,206,260)(H,207,261)(H,211,274)(H,212,275)(H,213,276)(H,214,277)(H,215,278)(H,216,279)(H,217,262)(H,218,263)(H,219,264)(H,220,280)(H,221,281)(H,222,282)(H,223,283)(H,224,284)(H,225,285)(H,226,286)(H,227,287)(H,228,288)(H,229,271)(H,230,272)(H,231,273)(H,265,266)(H,267,268)(H,269,270)(H,295,296)(H,297,298)(H,299,300)(H4,196,197,208)(H4,198,199,209)(H4,200,201,210);/q;+3/p-3/t118-,119-,120-,136-,137-,138-,139-,140-,141-,142-,143-,144-,145-,146-,147-,148-,149-,150-,151-,152-,153-,154+,155+,156+;/m0./s1/i;1-2 | StdInChI_comment = | StdInChIKey = XQKHPHFSWXYCLX-SNFBFVMKSA-K | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''⁶⁸Ga-Trivehexin'''<ref name="Quigley_2022">{{cite journal | vauthors = Quigley NG, Steiger K, Hoberueck S, Czech N, Zierke MA, Kossatz S, Pretze M, Richter F, Weichert W, Pox C, Kotzerke J, Notni J | title = PET/CT imaging of head-and-neck and pancreatic cancer in humans by targeting the "Cancer Integrin" αvβ6 with Ga-68-Trivehexin | journal = European Journal of Nuclear Medicine and Molecular Imaging | volume = 49 | issue = 4 | pages = 1136–1147 | date = March 2022 | pmid = 34559266 | pmc = 8460406 | doi = 10.1007/s00259-021-05559-x | doi-access = free }}</ref> is a radiotracer for positron emission tomography (PET), obtained by labeling the peptide conjugate Trivehexin<ref name="Quigley_2022" /> with the positron emitting radionuclide gallium-68 (⁶⁸Ga). ⁶⁸Ga-Trivehexin targets (i.e., binds to) the cell surface receptor αvβ6-integrin and accumulates in αvβ6-integrin-abundant tissues after intravenous (i.v.) application. ⁶⁸Ga-Trivehexin is thus applied for PET imaging of medical conditions associated with elevated αvβ6-integrin expression.

αvβ6-Integrin, the biological target of ⁶⁸Ga-Trivehexin, is a heterodimeric transmembrane cell adhesion receptor whose primary natural ligand is latency associated peptide (LAP)<ref name="Shi_2011">{{cite journal | vauthors = Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T, Springer TA | title = Latent TGF-β structure and activation | journal = Nature | volume = 474 | issue = 7351 | pages = 343–349 | date = June 2011 | pmid = 21677751 | pmc = 4717672 | doi = 10.1038/nature10152 }}</ref> in its complex with transforming growth factor beta 1 (TGF-β1).<ref>{{cite journal | vauthors = Moses HL, Roberts AB, Derynck R | title = The Discovery and Early Days of TGF-β: A Historical Perspective | journal = Cold Spring Harbor Perspectives in Biology | volume = 8 | issue = 7 | article-number = a021865 | date = July 2016 | pmid = 27328871 | pmc = 4930926 | doi = 10.1101/cshperspect.a021865 }}</ref><ref name="Deng_2024">{{cite journal | vauthors = Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, He J | title = TGF-β signaling in health, disease, and therapeutics | journal = Signal Transduction and Targeted Therapy | volume = 9 | issue = 1 | pages = 61 | date = March 2024 | pmid = 38514615 | pmc = 10958066 | doi = 10.1038/s41392-024-01764-w }}</ref> Binding of αvβ6-integrin to LAP releases<ref>{{cite journal | vauthors = Dong X, Zhao B, Iacob RE, Zhu J, Koksal AC, Lu C, Engen JR, Springer TA | title = Force interacts with macromolecular structure in activation of TGF-β | journal = Nature | volume = 542 | issue = 7639 | pages = 55–59 | date = February 2017 | pmid = 28117447 | pmc = 5586147 | doi = 10.1038/nature21035 | bibcode = 2017Natur.542...55D }}</ref> and thus, activates<ref>{{cite journal | vauthors = Worthington JJ, Klementowicz JE, Travis MA | title = TGFβ: a sleeping giant awoken by integrins | journal = Trends in Biochemical Sciences | volume = 36 | issue = 1 | pages = 47–54 | date = January 2011 | pmid = 20870411 | doi = 10.1016/j.tibs.2010.08.002 }}</ref> TGF-β1. In early-stage cancer, TGF-β1 acts as a tumor suppressor<ref>{{cite journal | vauthors = Tang B, Böttinger EP, Jakowlew SB, Bagnall KM, Mariano J, Anver MR, Letterio JJ, Wakefield LM | title = Transforming growth factor-beta1 is a new form of tumor suppressor with true haploid insufficiency | journal = Nature Medicine | volume = 4 | issue = 7 | pages = 802–807 | date = July 1998 | pmid = 9662371 | doi = 10.1038/nm0798-802 }}</ref> but can turn into a tumor promoter as cancers develop,<ref>{{cite journal | vauthors = Inman GJ | title = Switching TGFβ from a tumor suppressor to a tumor promoter | journal = Current Opinion in Genetics & Development | volume = 21 | issue = 1 | pages = 93–99 | date = February 2011 | pmid = 21251810 | doi = 10.1016/j.gde.2010.12.004 }}</ref><ref>{{cite journal | vauthors = Roberts AB, Wakefield LM | title = The two faces of transforming growth factor beta in carcinogenesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 15 | pages = 8621–8623 | date = July 2003 | pmid = 12861075 | pmc = 166359 | doi = 10.1073/pnas.1633291100 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Baba AB, Rah B, Bhat GR, Mushtaq I, Parveen S, Hassan R, Hameed Zargar M, Afroze D | title = Transforming Growth Factor-Beta (TGF-β) Signaling in Cancer-A Betrayal Within | journal = Frontiers in Pharmacology | volume = 13 | article-number = 791272 | date = 2022-02-28 | pmid = 35295334 | pmc = 8918694 | doi = 10.3389/fphar.2022.791272 | doi-access = free }}</ref> and furthermore induces fibrosis,<ref>{{cite journal | vauthors = Desmoulière A, Geinoz A, Gabbiani F, Gabbiani G | title = Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts | journal = The Journal of Cell Biology | volume = 122 | issue = 1 | pages = 103–111 | date = July 1993 | pmid = 8314838 | pmc = 2119614 | doi = 10.1083/jcb.122.1.103 }}</ref><ref>{{cite journal | vauthors = Evans RA, Tian YC, Steadman R, Phillips AO | title = TGF-beta1-mediated fibroblast-myofibroblast terminal differentiation-the role of Smad proteins | journal = Experimental Cell Research | volume = 282 | issue = 2 | pages = 90–100 | date = January 2003 | pmid = 12531695 | doi = 10.1016/S0014-4827(02)00015-0 }}</ref> particularly of the lung.<ref name="Ye_2021">{{cite journal | vauthors = Ye Z, Hu Y | title = TGF‑β1: Gentlemanly orchestrator in idiopathic pulmonary fibrosis (Review) | journal = International Journal of Molecular Medicine | volume = 48 | issue = 1 | date = July 2021 | pmid = 34013369 | pmc = 8136122 | doi = 10.3892/ijmm.2021.4965 }}</ref> As the likely most important activator of TGF-β1,<ref name="Deng_2024" /> αvβ6-integrin is often found overexpressed in tumors<ref name="Nieberler_2017" /> and fibrosis,<ref name="PMID 10025398" /> which is why ⁶⁸Ga-Trivehexin PET imaging is primarily relevant in this medical context.

==Chemistry==

=== Trivehexin precursor === Like most precursors used for radiolabeling with radioactive metal cations, Trivehexin is composed of a dedicated complex ligand (a so-called chelator) for kinetically inert binding of the ⁶⁸Ga^III ion, and the bioligand(s) for binding to αvβ6-integrin. The chelator comprised in Trivehexin is a triazacycloalkane with 3 phosphinic acid substituents, with the basic structure 1,4,7-triazacyclononane-1,4,7-triphosphinate<ref>{{cite journal | vauthors = Notni J, Šimeček J, Wester HJ | title = Phosphinic acid functionalized polyazacycloalkane chelators for radiodiagnostics and radiotherapeutics: unique characteristics and applications | journal = ChemMedChem | volume = 9 | issue = 6 | pages = 1107–1115 | date = June 2014 | pmid = 24700633 | doi = 10.1002/cmdc.201400055 }}</ref> (frequently abbreviated TRAP).<ref>{{cite journal | vauthors = Notni J, Šimeček J, Hermann P, Wester HJ | title = TRAP, a powerful and versatile framework for gallium-68 radiopharmaceuticals | journal = Chemistry | location = Weinheim an der Bergstrasse, Germany | volume = 17 | issue = 52 | pages = 14718–14722 | date = December 2011 | pmid = 22147338 | doi = 10.1002/chem.201103503 }}</ref><ref name="Steiger_2021">{{cite journal | vauthors = Steiger K, Quigley NG, Groll T, Richter F, Zierke MA, Beer AJ, Weichert W, Schwaiger M, Kossatz S, Notni J | title = There is a world beyond αvβ3-integrin: Multimeric ligands for imaging of the integrin subtypes αvβ6, αvβ8, αvβ3, and α5β1 by positron emission tomography | journal = EJNMMI Research | volume = 11 | issue = 1 | pages = 106 | date = October 2021 | pmid = 34636990 | pmc = 8506476 | doi = 10.1186/s13550-021-00842-2 | doi-access = free }}</ref><ref name="Baranyai_2015">{{cite journal | vauthors = Baranyai Z, Reich D, Vágner A, Weineisen M, Tóth I, Wester HJ, Notni J | title = A shortcut to high-affinity Ga-68 and Cu-64 radiopharmaceuticals: one-pot click chemistry trimerisation on the TRAP platform | journal = Dalton Transactions | location = Cambridge, England | volume = 44 | issue = 24 | pages = 11137–11146 | date = June 2015 | pmid = 25999035 | doi = 10.1039/C5DT00576K | hdl = 2437/234748 | hdl-access = free }}</ref> The αvβ6-integrin binding molecular unit is a cyclic nonapeptide with the amino acid sequence cyclo(YRGDLAYp(''N''Me)K).<ref name="Quigley_2022" />

In the Trivehexin molecule, three of these cyclopeptides are attached by covalent bonds to a single TRAP chelator core. Since TRAP possesses three equivalent carboxylic acids for conjugation of other molecular units via amide formation, Trivehexin is a C3-symmetrical molecule with its three peptide bioligands being fully equivalent. The peptides are attached to the chelator core via the terminal amine group of the side chains of ''N''-methyl lysine. Actually, the conjugation is not done by amide bonding directly, but involves prior functionalization of the peptide with a short molecular extension (a linker) bearing a terminal alkyne, and of TRAP with three linkers bearing terminal azides.<ref name="Baranyai_2015" /> These components are assembled by means of copper(I) catalyzed alkyne-azide cycloaddition (CuAAC, also known as Huisgen reaction, a Click chemistry reaction), giving rise to the three 1,3-triazole linkages in the ⁶⁸Ga-Trivehexin structure.<ref name="Quigley_2022" />

Trivehexin is manufactured and distributed by the German company TRIMT GmbH.<ref>{{Cite web |title=Peptides and building blocks |url=https://trimt.de/catalogue/ |access-date=2025-05-30 |website=TRIMT GmbH |language=en}}</ref>

=== ⁶⁸Ga radiolabeling === ⁶⁸Ga-Trivehexin is a radioactive drug. The radioactive atom, gallium-68 (⁶⁸Ga), decays with a half-life of approximately 68 min to the stable isotope zinc-68 (⁶⁸Zn), to 89% by β⁺ decay whereby a positron with a maximum kinetic energy of 1.9 MeV is emitted (the remaining 11% are EC decays). Due to the short half-life, ⁶⁸Ga-Trivehexin can not be manufactured long before use but the ⁶⁸Ga has to be introduced into the molecule shortly before application. This process is referred to as radiolabeling, and is done by complexation of the trivalent cation ⁶⁸Ga^III by the TRAP chelator in Trivehexin.

⁶⁸Ga^III is usually obtained from a dedicated mobile radionuclide source, a Gallium-68 generator, in form of a solution in dilute (0.04–0.1 M) hydrochloric acid (frequently and imprecisely referred to as "⁶⁸Ga chloride solution in HCl" despite it contains no species with a Ga–Cl bond but [⁶⁸Ga(H₂O)₆]³⁺ complex hydrate cations).<ref>{{Cite journal | title = Gallium(III) Ion Hydrolysis under Physiological Conditions | journal = Bulletin of the Korean Chemical Society | volume = 29 | issue = 2 | pages = 372–376 | date = 2008-02-20 | doi = 10.5012/bkcs.2008.29.2.372 | url = http://koreascience.or.kr/journal/view.jsp?kj=JCGMCS&py=2008&vnc=v29n2&sp=372 | language = en | issn = 0253-2964 }}</ref> For radiolabeling, the pH of the ⁶⁸Ga containing generator eluate has to be raised from its initial value (depending on HCl concentration, pH 1–1.5) to pH 2–3.5 <ref name="Wang_2024" /> using suitable buffers, such as sodium acetate. Then, Trivehexin (5–10 nmol) is added to the buffered ⁶⁸Ga-containing solution, and the mixture is briefly heated to 50–100&nbsp;°C (usually 2–3 min) to finalize the complexation reaction.<ref name="Quigley_2022" /><ref name="Wang_2024" />

==Use as medical imaging agent==

=== αvβ6-Integrin target ===

The abundance of αvβ6-integrin on most adult human cell types and respective tissues is low. It is however overexpressed in the context of several medical conditions, such as cancer<ref name="Nieberler_2017">{{cite journal | vauthors = Nieberler M, Reuning U, Reichart F, Notni J, Wester HJ, Schwaiger M, Weinmüller M, Räder A, Steiger K, Kessler H | title = Exploring the Role of RGD-Recognizing Integrins in Cancer. | journal = Cancers | volume = 9 | issue = 9 | pages = 116 | date = September 2017 | pmid = 28869579 | pmc = 5615331 | doi = 10.3390/cancers9090116 | doi-access = free }}</ref> or fibrosis,<ref name="PMID 10025398">{{cite journal | vauthors = Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, Rifkin DB, Sheppard D | title = The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis | journal = Cell | volume = 96 | issue = 3 | pages = 319–328 | date = February 1999 | pmid = 10025398 | doi = 10.1016/s0092-8674(00)80545-0 | doi-access = free }}</ref> particularly idiopathic pulmonary fibrosis.<ref name="Maher_2020">{{cite journal | vauthors = Maher TM, Simpson JK, Porter JC, Wilson FJ, Chan R, Eames R, Cui Y, Siederer S, Parry S, Kenny J, Slack RJ, Sahota J, Paul L, Saunders P, Molyneaux PL, Lukey PT, Rizzo G, Searle GE, Marshall RP, Saleem A, Kang'ombe AR, Fairman D, Fahy WA, Vahdati-Bolouri M | title = A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor. | journal = Respiratory Research | volume = 21 | issue = 1 | pages = 75 | date = March 2020 | pmid = 32216814 | pmc = 7099768 | doi = 10.1186/s12931-020-01339-7 | doi-access = free }}</ref>

In line with the finding that αvβ6-integrin is expressed by epithelial cells,<ref name="PMID 7673344">{{cite journal | vauthors = Breuss JM, Gallo J, DeLisser HM, Klimanskaya IV, Folkesson HG, Pittet JF, Nishimura SL, Aldape K, Landers DV, Carpenter W | title = Expression of the beta 6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling | journal = Journal of Cell Science | volume = 108 | issue = Pt 6 | pages = 2241–2251 | date = June 1995 | pmid = 7673344 | doi = 10.1242/jcs.108.6.2241 }}</ref> an elevated density of the protein is observed on the cell surfaces of many carcinomas (synonymous to cancers of epithelial origin).<ref name="Nieberler_2017" /><ref name="Niu_2017">{{cite journal | vauthors = Niu J, Li Z | title = The roles of integrin αvβ6 in cancer. | journal = Cancer Letters | volume = 403 | pages = 128–137 | date = September 2017 | pmid = 28634043 | doi = 10.1016/j.canlet.2017.06.012 }}</ref> Hence, ⁶⁸Ga-Trivehexin can be used for PET imaging of αvβ6-integrin positive cancers (i.e., those whose cells possess a sufficiently high density of αvβ6 on their surface), including but not limited to pancreatic ductal adenocarcinoma,<ref name="Steiger_2017">{{cite journal | vauthors = Steiger K, Schlitter AM, Weichert W, Esposito I, Wester HJ, Notni J | title = Perspective of αvβ6-Integrin Imaging for Clinical Management of Pancreatic Carcinoma and Its Precursor Lesions. | journal = Molecular Imaging | volume = 16 | issue = 1 | article-number = 1536012117709384 | date = January 2017 | pmid = 28627323 | pmc = 5480625 | doi = 10.1177/1536012117709384 | doi-access = free }}</ref> non-small cell lung cancer, squamous cell carcinomas (SCC) of different origin (most notably, oral and esophageal SCC), as well as breast, ovarian, and bladder cancer. In colorectal cancer, expression of αvβ6-integrin is higher in the more aggressive forms and correlated with reduced overall survival.<ref>{{cite journal | vauthors = Bates RC, Bellovin DI, Brown C, Maynard E, Wu B, Kawakatsu H, Sheppard D, Oettgen P, Mercurio AM | title = Transcriptional activation of integrin β6 during the epithelial-mesenchymal transition defines a novel prognostic indicator of aggressive colon carcinoma | journal = The Journal of Clinical Investigation | volume = 115 | issue = 2 | pages = 339–347 | date = February 2005 | pmid = 15668738 | pmc = 544606 | doi = 10.1172/JCI23183 }}</ref>

⁶⁸Ga-Trivehexin has a high binding affinity to αvβ6-integrin (IC₅₀ = 0.047 nM). Its affinity to other RGD-binding integrins is much lower (IC₅₀ for αvβ3, αvβ8, and α5β1 are 2.7, 6.2, and 22 nM, respectively; note that for IC₅₀, higher values mean lower affinity),<ref name="Quigley_2022" /> resulting in a high selectivity for αvβ6-integrin.

===Imaging procedure===

Since ⁶⁸Ga is a positron emitter, ⁶⁸Ga-Trivehexin is applicable for PET imaging. However, PET is rarely used as a standalone imaging technique these days. Most clinics use PET/CT or even PET/MRI systems that acquire morphological and functional images in a single workflow and thus, provide more detailed and useful medical information to the physician.

For clinical PET/CT diagnostics, an activity in the range of 80–150 MBq ⁶⁸Ga-Trivehexin is injected intravenously (i.v.).<ref name="Quigley_2021" /><ref name="Rehm_2024a" /> The tracer then distributes with the blood flow and moves into tissues by diffusion, where it specifically binds to its target αvβ6-integrin, while an excess is excreted via the kidneys and the urine. As a result, ⁶⁸Ga-Trivehexin and, therefore, the positron-emitting radionuclide ⁶⁸Ga, is preferably accumulated by αvβ6-integrin abundant tissues (for example, tumor tissue). Next, a PET/CT scanner is used to detect the ''gamma radiation'' which is generated by the annihilation of the positrons emitted by ⁶⁸Ga ('''''not''''' the actual positrons, which do not leave the body but travel only a few millimetres through the tissue). The spatial distribution of the annihilation events is reconstructed from the raw detector data (referred to as listmode data), which eventually delivers a 3-dimensional data set of radioactivity distribution in the body. These data allow the visualization of αvβ6-integrin positive tissues as 2-dimensional tomographic images or 3-dimensional volume rendering. Typically, the PET/CT imaging is performed 45–60 minutes after the i.v. administration of ⁶⁸Ga-Trivehexin.<ref name="Rehm_2024a" />

=== Cancers imaging === [[File:Ga-68-Trivehexin PDAC Liver Metastases EJNMMI 2022.png|thumb|⁶⁸Ga-Trivehexin PET image of a female patient with pancreatic ductal adenocarcinoma (PDAC), shown as maximum intensity projections in frontal (left) and lateral (right) position. The primary tumor in the pancreatic head (labeled 'Primary') and a total of 7 liver metastases (the 3 largest are labeled Met#1, Met#2 and Met#3) are clearly delineated. Due to renal excretion, a prominent signal is observed in the kidneys (center of images) and in the contents of the urinary bladder (lower image regions).<ref name="Quigley_2022" />]] ⁶⁸Ga-Trivehexin has not yet obtained a marketing approval. It is used for clinical imaging of αvβ6-integrin expression in experimental settings.

==== Pancreatic cancer ==== First-in-human application of different αvβ6-integrin radiotracers has demonstrated that ⁶⁸Ga-Trivehexin performed especially well in detecting pancreatic cancer, showing high uptake in tumor lesions and low background in the gastrointestinal tract (GI tract) (see image).<ref name="Kimura_2023">{{cite journal | vauthors = Kimura RH, Iagaru A, Guo HH | title = Mini review of first-in-human integrin αvβ6 PET tracers | journal = Frontiers in Nuclear Medicine | volume = 3 | issue = 3 | article-number = 1271208 | date = October 2023 | pmid = 39355045 | pmc = 11440954 | doi = 10.3389/fnume.2023.1271208 | doi-access = free }}</ref> Since its introduction,<ref name="Quigley_2022" /> ⁶⁸Ga-Trivehexin has been used predominantly for PET/CT imaging of pancreatic ductal adenocarcinoma (PDAC), for example, in single cases <ref name="Quigley_2021">{{cite journal | vauthors = Quigley NG, Czech N, Sendt W, Notni J | title = PET/CT imaging of pancreatic carcinoma targeting the "cancer integrin" αvβ6 | journal = European Journal of Nuclear Medicine and Molecular Imaging | volume = 48 | issue = 12 | pages = 4107–4108 | date = June 2021 | pmid = 34109438 | pmc = 8484182 | doi = 10.1007/s00259-021-05443-8 | language = EN | doi-access = free }}</ref><ref name="Rehm_2024">{{cite journal | vauthors = Rehm J, Winzer R, Notni J, Hempel S, Distler M, Folprecht G, Kotzerke J | title = Concomitant metastatic head-and-neck cancer and pancreatic cancer assessed by αvβ6-integrin PET/CT using ⁶⁸Ga-Trivehexin: incidental detection of a brain metastasis. | journal = European Journal of Nuclear Medicine and Molecular Imaging | volume = 51 | issue = 11 | pages = 3469–3471 | date = September 2024 | pmid = 38771514 | pmc = 11368998 | doi = 10.1007/s00259-024-06750-6 | doi-access = free }}</ref> and two cohorts (12 and 44 patients, respectively) <ref name="Das_2024">{{cite journal | vauthors = Das SS, Ahlawat S, Thakral P, Malik D, Simecek J, Cb V, Koley M, Gupta J, Sen I | title = Potential Efficacy of ⁶⁸Ga-Trivehexin PET/CT and Immunohistochemical Validation of αvβ6 Integrin Expression in Patients With Head and Neck Squamous Cell Carcinoma and Pancreatic Ductal Adenocarcinoma. | journal = Clinical Nuclear Medicine | volume = 49 | issue = 8 | pages = 733–740 | date = May 2024 | pmid = 38768077 | doi = 10.1097/RLU.0000000000005278 | language = EN }}</ref><ref name="Rehm_2024a">{{cite journal | vauthors = Rehm J, Winzer R, Pretze M, Mueller J, Notni J, Hempel S, Distler M, Folprecht G, Kotzerke J | title = αvβ6-integrin targeted PET/CT imaging in pancreatic cancer patients using ⁶⁸Ga-Trivehexin | journal = Frontiers in Nuclear Medicine | volume = 4 | issue = 4 | article-number = 1487602 | date = November 2024 | pmid = 39618940 | pmc = 11604418 | doi = 10.3389/fnume.2024.1487602 | doi-access = free }}</ref> of suspected or known PDAC.

==== Breast cancer ==== The feasibility of ⁶⁸Ga-Trivehexin PET imaging of breast cancer (BC) was demonstrated in a case of triple-negative BC.<ref>{{Cite journal |vauthors=Alahmad T, Alfeeli M, Sadeq A, Marafi F |date=2025-05-15 |title=Triple Negative Breast Cancer and 68Ga-Trivehexin: A Glance of Hope |url=https://journals.lww.com/10.1097/RLU.0000000000005963 |journal=Clinical Nuclear Medicine |language=en |doi=10.1097/RLU.0000000000005963 |issn=0363-9762 |pmid=40369806|url-access=subscription }}</ref> Another report suggested that ⁶⁸Ga-Trivehexin PET/CT might offer superior detection efficacy for breast cancer compared to ¹⁸F-FDG PET/CT.<ref>{{cite journal | vauthors = Liu Z, Li C, Xiao Z, Lu N, He Y | title = 68Ga-Trivehexin PET/CT Enhances Detection of Small Primary Lesions Than 18F-FDG PET/CT in Breast Cancer | journal = Clinical Nuclear Medicine | date = July 2025 | pmid = 40644590 | doi = 10.1097/RLU.0000000000006031 }}</ref> Furthermore, in progesterone- and estrogen-receptor negative BC with elevated Ki67 proliferation index and strong E-cadherin, ⁶⁸Ga-Trivehexin PET identified several ¹⁸F-FDG-avid lymph nodes as false positives.<ref>{{cite journal |vauthors=Kömek H, Güzel Y, Kaplan İ, Yilmaz EE, Can C |date=November 2024 |title=Superiority of 68 Ga-Trivehexin PET/CT Over 18 F-FDG PET/CT in the Evaluation of Lymph Nodes in Patients With Breast Cancer |journal=Clinical Nuclear Medicine |volume=50 |issue=3 |pages=e175–e177 |doi=10.1097/RLU.0000000000005585 |pmid=39601487}}</ref> In a patient with lobular BC and pancreatic neuroendocrine tumor (PNET), ⁶⁸Ga-Trivehexin selectively showed a PET signal only in the lobular carcinoma, while the metabolic tracer ¹⁸F-FGD and the neuroendocrine tumor tracer ⁶⁸Ga-DOTATATE yielded PET signals for both the BC and PNET lesions.<ref>{{Cite journal | vauthors = Alan Selçuk N, Akçay K, Yaprak O, Kalaycı M, Kabasakal L, Beydağı G | title = Cancer Integrin Imaging with [68Ga]Ga-Trivehexin PET/CT for a Patient with Breast Cancer and Neuroendocrine Neoplasm: A Case of Both (18F)FDG PET/CT and [68Ga]Ga-DOTATATE Positive but Integrin avβ6 Negative Lesion on [68Ga]Ga-Trivehexin PET | journal = Molecular Imaging and Radionuclide Therapy | date = 2025-05-23 | doi = 10.4274/mirt.galenos.2024.60320 | url = https://mirt.tsnmjournals.org/articles/cancer-integrin-imaging-with-lesssupgreater68lesssupgreatergaga-trivehexin-petct-for-a-patient-with-breast-cancer-and-neuroendocrine-neoplasm-a-case-of-both-lesssupgreater18lesssupgreaterffdg-petct-and-lesssupgreater68lesssupgreatergaga-dotatate-positive-but-integrin-avlessstronggreaterblessstronggreater6-negative-lesion-on-lesssupgreater68lesssupgreatergaga-trivehexin-pet/doi/mirt.galenos.2024.60320 | pmc = 12134958 }}</ref> [[File:Ga-68-Trivehexin vs FDG Non Small Cell Lung Cancer Brain Metastases AdvSci 2025 He-et-al.png|thumb|Representative ⁶⁸Ga-Trivehexin PET/CT (left) of a 55-year-old woman with lung adenocarcinoma and multiple metastatic lesions, compared with ¹⁸F-FDG PET/CT (right).<ref name="Wu_2025b" /> Both images show maximum intensity projections (MIPs). Yellow arrows: Primary tumor (SUV_max: 20.7 for ⁶⁸Ga-Trivehexin, vs. 12.5 for ¹⁸F-FDG). Red arrows: Metastatic lesions including lymph node metastases (SUV_max: 23.9 vs 7.4). Blue arrows: Brain metastases (SUV_max: 3.4– 6.9 vs. 9.8–12.9). Green arrows: Liver metastases (SUV_max: 22.7 vs. 7.1). Pink arrows: Bone metastases (SUV_max: 20.4 vs. 11.2).]]

==== Lung Cancer ==== A prospective clinical study (NCT05835570)<ref>{{ClinicalTrialsGov|NCT05835570|Integrin αvβ6-targeted PET in Malignant Tumors }}</ref> involving 58 participants with non-small cell lung cancer (NSCLC) compared the diagnostic performance of ⁶⁸Ga-Trivehexin PET/CT with ¹⁸F-FDG PET/CT.<ref name="Wu_2025b">{{cite journal | vauthors = Wu H, Li C, Li L, Tian Y, Xiao Z, Huang Y, Zhong J, Huang J, Chen Q, He Y | title = Integrin αvβ6-Targeted PET/CT Imaging of Non-Small Cell Lung Cancer with [⁶⁸Ga]Ga-Trivehexin: Improved Preoperative Lymph Node Staging and Association with Immunohistochemistry | journal = Advanced Science | article-number = e08225 | date = September 2025 | pmid = 40899568 | doi = 10.1002/advs.202508225 | doi-access = free }}</ref> Both radiotracers showed similar diagnostic accuracy (100%, 58/58) for the detection of primary tumors. The sensitivity for detection of lymph node metastases was comparable for ⁶⁸Ga-Trivehexin (80%) and ¹⁸F-FDG (72%), but ⁶⁸Ga-Trivehexin showed a higher specificity (93.8%) and accuracy (91.2%) than ¹⁸F-FDG (62.5% and 64.2%, respectively). Sensitivity for detecting brain metastasis was 92.3% for ⁶⁸Ga-Trivehexin and 38.5% for ¹⁸F-FDG, mainly because of the high glucose consumption of normal brain tissue, which usually results in a high physiological uptake of ¹⁸F-FDG in the brain, generating a strong background signal which frequently obscures brain metastases in PET images (see image).

Application of ⁶⁸Ga-Trivehexin PET was reported for single cases of other, rare forms of lung cancer, such as bronchial mucoepidermoid carcinoma<ref name="Wu_20242">{{cite journal |vauthors=Wu H, Li L, Xiao Z, Li C, He Y |date=November 2024 |title=αvβ6-integrin targeted [⁶⁸Ga]Ga-Trivehexin PET/CT imaging of a rare bronchial mucoepidermoid carcinoma |journal=European Journal of Nuclear Medicine and Molecular Imaging |volume=52 |issue=4 |pages=1291–1292 |doi=10.1007/s00259-024-06974-6 |pmid=39500808 |doi-access=free}}</ref> and mucinous lung adenocarcinoma.<ref name="Wu_20252">{{cite journal |vauthors=Wu H, Li L, Xiao Z, Chen Q, Li C, He Y |date=March 2025 |title=[⁶⁸Ga]Ga-Trivehexin PET/CT imaging of integrin-αvβ6 expression in concomitant mucinous lung adenocarcinoma and idiopathic pulmonary fibrosis |journal=European Journal of Nuclear Medicine and Molecular Imaging |doi=10.1007/s00259-025-07146-w |pmid=40042637}}</ref>

==== Head-and-neck cancer ==== thumb|⁶⁸Ga-Trivehexin PET/CT of head-and-neck cancer with brain metastasis.<ref name="Rehm_2024" /> In a cohort of 20 suspected (19 confirmed) head-and-neck squamous cell carcinoma (HNSCC) cases, ⁶⁸Ga-Trivehexin PET had a higher sensitivity (92.5%), positive predictive value (PPV, 100%), and accuracy (93%) than the standard ¹⁸F-FDG PET, for which sensitivity, PPV, and accuracy were 90%, 93.1%, and 84.3%, respectively.<ref name="Das_2024" /> ⁶⁸Ga-Trivehexin was furthermore applied in a case of tonsillar carcinoma metastasized to the brain (see image).<ref name="Rehm_2024" />

==== Other cancers ==== ⁶⁸Ga-Trivehexin was also applied in cases of recurrent parathyroid carcinoma<ref>{{Cite journal |vauthors=Kuyumcu S, Kubat Uzum A, Isik EG, Sanli Y, Denizmen Zorba D |date=2025-05-15 |title=Detection of Recurrent Parathyroid Cancer Using 68Ga-Trivehexin PET/CT |url=https://journals.lww.com/10.1097/RLU.0000000000005735 |journal=Clinical Nuclear Medicine |language=en |doi=10.1097/RLU.0000000000005735 |issn=0363-9762 |pmid=40369809|url-access=subscription }}</ref> and papillary thyroid carcinoma.<ref name="Singhal_2024">{{cite journal |vauthors=Singhal T, Agrawal K, Mandal S, Parida GK |date=November 2024 |title=Cancer-Specific Integrin Imaging With ⁶⁸Ga-Trivehexin: A Potential Imaging for Accurate Staging of Thyroid Malignancy. |journal=Clinical Nuclear Medicine |volume=50 |issue=3 |pages=e168–e170 |doi=10.1097/RLU.0000000000005557 |pmid=39499025 |doi-access=free}}</ref>

=== Imaging of benign and non-oncological conditions ===

==== Parathyroid adenoma (PTA) ==== In the context of primary hyperparathyroidism (PHPT), ⁶⁸Ga-Trivehexin PET/CT was successfully applied for PET imaging of disseminated parathyroid adenoma with a detection rate of 94.1%,<ref name="Kuyumcu_2024">{{cite journal |vauthors=Kuyumcu S, Denizmen D, Has-Simsek D, Poyanli A, Uzum AK, Buyukkaya F, Isik EG, Onder S, Aksakal N, Ozkan ZG, Sanli Y |date=July 2024 |title=⁶⁸Ga-Trivehexin PET/CT: a promising novel tracer for primary hyperparathyroidism |journal=European Journal of Nuclear Medicine and Molecular Imaging |volume=51 |issue=13 |pages=3912–3923 |doi=10.1007/s00259-024-06846-z |pmc=11527967 |pmid=39028425 |doi-access=free}}</ref> and furthermore for delineation of osteolysis-associated brown tumors which occur as a result of persistent hyperparathyroidism.<ref>{{cite journal |vauthors=Kar S, Lele VR, Shaikh N |date=May 2025 |title=68Ga-Trivehexin Uptake in Brown Tumors in Hyperparathyroidism: A Novel Finding |journal=Clinical Nuclear Medicine |doi=10.1097/RLU.0000000000005989 |pmid=40392150}}</ref> [[File:Ga-68-Trivehexin Parathyroid Adenoma Compared to Tc-99m-Sestamibi EJNMMI 2024.png|none|thumb|655x655px|Imaging of a patient with primary hyperparathyroidism (PHPT).<ref name="Kuyumcu_2024" /> A single parathyroid adenoma lesion (marked with arrows labeled 'PTA') is seen in the ⁶⁸Ga-Trivehexin PET MIP (maximum intensity projection) and a PET/CT axial (transverse) slice though the lesion. The same patient was diagnosed using the imaging agent ^99mTc-Sestamibi, which is standard-of-care for PHPT diagnostics. The PTA is not seen on planar scintigraphy or SPECT/CT images. Instead, a moderate physiological uptake is observed in the healthy thyroid (marked with green arrows).]]

==== Fibrosis ==== In accordance with the known expression of αvβ6-integrin in early lung fibrosis,<ref name="Ye_2021" /> ⁶⁸Ga-Trivehexin was used for PET/CT imaging of idiopathic pulmonary fibrosis (IPF).<ref>{{Cite web | title = Lung fibrosis: radiopharmaceutical improves diagnosis and monitoring | url = https://healthcare-in-europe.com/en/news/lung-fibrosis-radiopharmaceutical-diagnosis-monitoring.html | access-date = 2025-03-24 | website = healthcare-in-europe.com | language = en }}</ref> In explorative studies, ⁶⁸Ga-Trivehexin could generate an IPF-specific PET signal while the same tissue areas were PET-negative using the standard metabolic PET tracer ¹⁸F-FDG.<ref name="Wu_2025">{{cite journal |vauthors=Wu H, Li L, Xiao Z, Chen Q, Li C, He Y |date=March 2025 |title=[⁶⁸Ga]Ga-Trivehexin PET/CT imaging of integrin-αvβ6 expression in concomitant mucinous lung adenocarcinoma and idiopathic pulmonary fibrosis |journal=European Journal of Nuclear Medicine and Molecular Imaging |doi=10.1007/s00259-025-07146-w |pmid=40042637}}</ref><ref>{{cite journal | vauthors = Kuyumcu S, Denizmen Zorba D, Özkan ZG | title = ⁶⁸Ga-Trivehexin PET/CT uptake in malignant and fibrotic lung tissue: refining diagnostic applications | journal = European Journal of Nuclear Medicine and Molecular Imaging | date = March 2025 | pmid = 40082263 | doi = 10.1007/s00259-025-07193-3 | doi-access = free | pmc = 12316737 }}</ref> ⁶⁸Ga-Trivehexin PET scans displayed an uptake of SUV_max = 5.53 in fibrotic lung areas and thus enabled clear differentiation of fibrotic from non-fibrotic lung tissue.<ref name="Wu_2025" />

===Safety===

Like for other radioactive imaging agents in medicine, the applied amounts of radioactivity are so low that radiation-related adverse effects are very unlikely to occur, and have not been observed in practice. Consistent with the "tracer principle", the amount of pharmacologically active compound injected to a patient in the course of such an examination is extremely low. Adverse events, such as toxicity or allergic reactions, are thus highly improbable. No adverse or clinically detectable pharmacologic effects were observed following intravenous administration of ⁶⁸Ga-Trivehexin when administered to cancer patients, and there were no significant changes in vital signs, laboratory study results, or electrocardiograms.<ref name="Rehm_2024a" /> In a study involving healthy volunteers, researchers again reported no adverse or clinically detectable pharmacologic effects and no significant changes in vital signs.<ref name="Wang_2024">{{cite journal | vauthors = Wang B, Jiang Y, Zhu J, Wu H, Wu J, Li L, Huang J, Xiao Z, He Y | title = Fully-automated production of [⁶⁸Ga]Ga-Trivehexin for clinical application and its biodistribution in healthy volunteers. | journal = Frontiers in Oncology | volume = 14 | article-number = 1445415 | date = August 2024 | pmid = 39156699 | pmc = 11327152 | doi = 10.3389/fonc.2024.1445415 | doi-access = free }}</ref>

== References == {{reflist}}

Category:Positron emission tomography Category:Amides Category:Chelating agents Category:Nine-membered rings Category:Gallium Category:Phosphinates Category:Isotopes of gallium Category:Nonapeptides Category:Triazoles