Ga-68-Trivehexin

Ga-68-Trivehexin
Identifiers
  • [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+)
PubChem CID
UNII
Chemical and physical data
FormulaC195H288GaN54O51P3
Molar mass4367.420 g·mol−1
3D model (JSmol)
  • 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]
  • InChI=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
  • Key:XQKHPHFSWXYCLX-SNFBFVMKSA-K

68Ga-Trivehexin[1] is a radiotracer for positron emission tomography (PET), obtained by labeling the peptide conjugate Trivehexin[1] 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)[2] in its complex with transforming growth factor beta 1 (TGF-β1).[3][4] Binding of αvβ6-integrin to LAP releases[5] and thus, activates[6] TGF-β1. In early-stage cancer, TGF-β1 acts as a tumor suppressor[7] but can turn into a tumor promoter as cancers develop,[8][9][10] and furthermore induces fibrosis,[11][12] particularly of the lung.[13] As the likely most important activator of TGF-β1,[4] αvβ6-integrin is often found overexpressed in tumors[14] and fibrosis,[15] which is why 68Ga-Trivehexin PET imaging is primarily relevant in this medical context.

Chemistry

Trivehexin, the radiolabeling 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 68GaIII 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[16] (frequently abbreviated TRAP).[17][18][19] The αvβ6-integrin binding molecular unit is a cyclic nonapeptide with the amino acid sequence cyclo(YRGDLAYp(NMe)K).[1]

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.[19] 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.[1]

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 68GaIII by the TRAP chelator in Trivehexin.

68GaIII 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).[20] 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 [21] 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 °C (usually 2–3 min) to finalize the complexation reaction.[1][22]

Use as medical imaging agent

αvβ6-Integrin as molecular 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[14] or fibrosis,[15] particularly idiopathic pulmonary fibrosis.[23]

In line with the finding that αvβ6-integrin is expressed by epithelial cells,[24] an elevated density of the protein is observed on the cell surfaces of many carcinomas (synonymous to cancers of epithelial origin).[14][25] 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,[26] 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.

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),[1] 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.).[27][28] 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.[28]

PET/CT imaging of cancers

68Ga-Trivehexin has not yet obtained a marketing approval. It is used for clinical imaging of αvβ6-integrin expression in experimental settings. 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).[29] 68Ga-Trivehexin has been used for clinical PET/CT imaging in single cases [27][30] and two cohorts (12 and 44 patients, respectively) [31][28] of suspected or known pancreatic ductal adenocarcinoma, as well as in cases of tonsillar carcinoma metastasized to the brain,[30] of bronchial mucoepidermoid carcinoma,[32] of disseminated parathyroid adenoma in the context of the diagnosis of primary hyperparathyroidism (PHPT),[33] of papillary thyroid carcinoma,[22] and of breast cancer.[34] 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 predicitive 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.[31]

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.[28] In a study involving healthy volunteers, researchers again reported no adverse or clinically detectable pharmacologic effects and no significant changes in vital signs.[21]

References

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Information related to Ga-68-Trivehexin

Ga-68-Trivehexin
Index: pl ar de en es fr it arz nl ja pt ceb sv uk vi war zh ru af ast az bg zh-min-nan bn be ca cs cy da et el eo eu fa gl ko hi hr id he ka la lv lt hu mk ms min no nn ce uz kk ro simple sk sl sr sh fi ta tt th tg azb tr ur zh-yue hy my ace als am an hyw ban bjn map-bms ba be-tarask bcl bpy bar bs br cv nv eml hif fo fy ga gd gu hak ha hsb io ig ilo ia ie os is jv kn ht ku ckb ky mrj lb lij li lmo mai mg ml zh-classical mr xmf mzn cdo mn nap new ne frr oc mhr or as pa pnb ps pms nds crh qu sa sah sco sq scn si sd szl su sw tl shn te bug vec vo wa wuu yi yo diq bat-smg zu lad kbd ang smn ab roa-rup frp arc gn av ay bh bi bo bxr cbk-zam co za dag ary se pdc dv dsb myv ext fur gv gag inh ki glk gan guw xal haw rw kbp pam csb kw km kv koi kg gom ks gcr lo lbe ltg lez nia ln jbo lg mt mi tw mwl mdf mnw nqo fj nah na nds-nl nrm nov om pi pag pap pfl pcd krc kaa ksh rm rue sm sat sc trv stq nso sn cu so srn kab roa-tara tet tpi to chr tum tk tyv udm ug vep fiu-vro vls wo xh zea ty ak bm ch ny ee ff got iu ik kl mad cr pih ami pwn pnt dz rmy rn sg st tn ss ti din chy ts kcg ve
Prefix: a b c d e f g h i j k l m n o p q r s t u v w x y z 0 1 2 3 4 5 6 7 8 9

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