Gallium labeled NOTA-based conjugates for peptide receptor-mediated medical imaging

Abstract

We report a straightforward and efficient synthetic strategy for the synthesis of three model glycine-arginine-glycine-aspartic acid-glycine (GRGDG) conjugates based on derivatives of NOTA and of their Ga(III) complexes targeted to the integrin α(ν)β(3) receptor. (71)Ga NMR spectroscopy showed that the Ga(III)-labeled conjugates are highly stable in aqueous solution. The (67)Ga-labeled conjugates proved to have high kinetic stability and showed a weak but specific binding to the receptors in a U87MG-glioblastoma cell line.

Peptide synthesis, characterization and 68Ga-radiolabeling of NOTA-conjugated ubiquicidin fragments for prospective infection imaging with PET/CT

“…The relatively straight-forward radiolabeling of most bi-functional chelators makes these kinds of tracers suitable for mass production in kit form that can be distributed to, and used by staff at hospitals and clinics where an on-site radionuclide generator is present [9,10].…”

“…However, more recently, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) has been investigated as a potential bifunctional chelator for use in tracers, as, unlike DOTA, efficient radiolabeling of NOTA tracers can occur without heating to temperatures which risk damaging targeting vectors such as peptides [9][10][11]. Due to the smaller dimensions of the macrocyclic cavity of NOTA, as compared to DOTA, the stability of a NOTA chelate containing a small cation such as 68 Ga is greater [10]. This leads to greater thermodynamic and kinetic stability [12,13], which is advantageous as it makes the NOTA-peptide conjugate both easier to label and more resistant to trans-metallation in the body [9,13].…”

“…If, as in most reported cases (for instance DOTATATE), the NOTA or DOTA chelator is linked to the peptide via one of the acid groups (as is also reported herein) the conjugation ability of the chelator is reduced as compared to linking to the peptide via the carbon backbone. However studies have shown that the chelation is sufficient for in vivo use and stable for 24 h even if challenged with a 10 4 fold molar excess of DTPA [10,12]. When conjugating bi-functional chelators to a chemically synthesized peptide fragment such as UBI29-41 (TGRAKRRMQYNRR), different approaches are possible.…”

Gallium(III) complexes of NOTA‐bis (phosphonate) conjugates as PET radiotracers for bone imaging

“…The size of coordination cavity imposed by the nine-member macrocyclic ring corresponds very well to size of Ga III ion. Among them (by analogy with the most commonly used ligands in DOTA-like family, the DOTAmonoamides), NOTA-monoamides appear as an emerging class of ligands owing to their easy synthesis and potential easiness of introduction of bifunctionality through amide formation (30)(31)(32)(33). Thus, a number of NOTA-like ligands have been investigated as promising chelators for 68 Ga (1,10).…”

Radiolabeled Dendrimers as Potential PET Agents for Molecular Imaging of Tumor Angiogenesis

“…At physiological conditions, the human transferrin has a high binding affinity for Ga 3+ given by log KST = 20.3 [60]. Thus, radiolabeling of 68 Ga is best achieved by using bifunctional chelators which can strongly chelate the gallium ion and are covalently bound to targeting vectors [61,62]. The most widely used bifunctional chelator for 68 Ga radionuclide labeling is DOTA [63].…”