Synthesis and evaluation of zirconium-89 labelled and long-lived GLP-1 receptor agonists for PET imaging

Enzyme mediated incorporation of zirconium-89 or copper-64 into a fragment antibody for same day imaging of epidermal growth factor receptor

“…35 In addition, the [ 89 Zr]Zr IV complexes that are formed are more resistant to ligand exchange. 35,36 To develop the [ 64 Cu]Cu IIbased agents a derivative of the macrobicyclic sarcophagine (sar = 3,6,10,13,16,19-hexaazabicyclo-[6.6.6]icosane) cage amine ligand, MeCOSar (Figure 2), with an N-terminal glycine residue was used as radiolabeling can be achieved rapidly at room temperature to give high radiochemical yields and the complexes formed are stable in vivo. [37][38][39][40][41] The new conjugates were evaluated in an EGFR positive A431 xenograft model and compared to conjugates of the full-length anti-EGFR IgG antibody, cetuximab, radiolabeled using the same metal chelators.…”

Imaging Somatostatin Positive Tumors with Tyr3-Octreotate/Octreotide Conjugated to Desferrioxamine B Squaramide Radiolabeled with either Zirconium-89 or Gallium-68

“…29,33 Zirconium(IV) complexes of the squaramide ester derivative, DFOSqOEt, are more resistant to ligand exchange than zirconium(IV) complexes with DFO derivatives prepared using the isothiocyanate derivative, H 3 DFO-C(S)-NH-PhNCS, and have better solubility in aqueous mixtures. 34,35 The coupling of squaramide ethyl esters to the amino groups of peptides is straightforward and does not involve the use of additional coupling agents. In this work, we extend the approach to attach the cyclic peptides Tyr 3 -octreotate and Tyr 3 -octreotide to DFOSq.…”

“…In recent work, aimed at preparing receptor targeting ligands that can be radiolabeled with either zirconium-89 or gallium-68, we used a version of the bacterial siderophore, desferrioxamine B (H 3 DFO) that has been modified by the addition of a squaramide ethyl ester functional group to give H 3 DFOSquaramide (H 3 DFOSq) to attach glutamate-ureido-lysine small molecules that target prostate-specific membrane antigen . The potential of derivatives of H 3 DFO to coordinate gallium-67 and gallium-68 radionuclides has been demonstrated previously. − For example, a [ 67 Ga]­[Ga­(DFO)] complex was demonstrated as being sufficiently stable in human serum for 2 days. , Zirconium­(IV) complexes of the squaramide ester derivative, DFOSqOEt, are more resistant to ligand exchange than zirconium­(IV) complexes with DFO derivatives prepared using the isothiocyanate derivative, H 3 DFO-C­(S)-NH-PhNCS, and have better solubility in aqueous mixtures. , The coupling of squaramide ethyl esters to the amino groups of peptides is straightforward and does not involve the use of additional coupling agents. In this work, we extend the approach to attach the cyclic peptides Tyr 3 -octreotate and Tyr 3 -octreotide to DFOSq.…”

Comparison of the Tissue Distribution of a Long-Circulating Glucagon-like Peptide-1 Agonist Determined by Positron Emission Tomography and Quantitative Whole-Body Autoradiography

“…15 In our previous work, we have developed and optimized the first 89 Zr PET tracer of a protracted GLP-1R receptor agonist peptide and demonstrated that it retains a high affinity to both GLP-1R and albumin and also similar in vivo pharmacodynamic properties after conjugation. 16 Here, we use this model peptide to present the first tissue distribution comparison of a long-circulating peptide PET tracer with QWBA to validate PET as a non-invasive method in drug development. We investigate the influence of the chelator modification on PK, its metabolic stability, and how it shifted the tracer distribution 7 days after tracer administration via intravenous and subcutaneous routes.…”

“…Semaglutide and liraglutide are potent glucagon-like peptide-1 receptor (GLP-1R) agonist peptides, which contain a fatty acid group that binds to serum albumin, leading to a protracted drug release and pharmacokinetics (PK) . In our previous work, we have developed and optimized the first 89 Zr PET tracer of a protracted GLP-1R receptor agonist peptide and demonstrated that it retains a high affinity to both GLP-1R and albumin and also similar in vivo pharmacodynamic properties after conjugation …”