Investigation of Fluorine-18 Labelled Peptides for Binding to Cholecystokinin-2 Receptors with High Affinity

• Published in: International journal of peptide research and therapeutics Vol. 28; no. 1
• Main Authors: Khan, Naeem-Ul-Haq, Corlett, Alicia, Hutton, Craig A., Haskali, Mohammad B.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 2022; Springer Nature B.V
• Subjects: Affinity; Animal Anatomy; Biochemistry; Biomedical and Life Sciences; Cholecystokinin; Esters; Fluorine; Gastrin; Histology; Labeling; Life Sciences; Ligands; Molecular Medicine; Morphology; N-Terminus; Peptides; Pharmaceutical Sciences/Technology; Pharmacology/Toxicology; Polymer Sciences; Positron emission tomography; Small cell lung carcinoma; Thyroid cancer; Cholecystokinin-2 receptors; Radionuclides; CCK-2R; Radiolabeling; Fluorine-18; Positron emission tomography; Theranostics
• ISSN: 1573-3149; 1573-3904
• DOI: 10.1007/s10989-021-10310-z

Many cancers of neuroendocrine origin overexpress cholecystokinin-2 receptors (CCK-2R) including medullary thyroid cancer, small cell lung cancer and other lung carcinoids. Fluorine-18 labelled peptides targeting CCK-2R enable direct visualization and quantification of this receptor in vivo using positron emission tomography imaging. CP04
1
and MG11
2
are two previously described truncated peptides derived from the native CCK-2R hormone ligand, gastrin. The
N
-terminus of the MG11
2
octopeptide was chemically modified with various fluorine containing aromatic (4-fluorobenzoate), heterocyclic (6-fluoronicotinate) and aliphatic (2-fluoropropionate) moieties. To assess the impact these modifications had on CCK-2R binding, ligand-binding assays were conducted using A431 cells overexpressing human CCK-2R. MG11
2
modified by 4-fluorobenzoate (FB-MG11
3
) demonstrated the highest binding affinity (0.20 nM) followed by MG11
2
modified by 6-fluoronicotinate (FNic-MG11
4
; 0.74 nM) and 2-fluoropropionate (FP-MG11
5
; 1.80 nM), respectively. Whilst indirect labelling of MG11
2
using fluorine-18 labelled activated esters of fluorobenzoate and 6-fluoronicotinate was unsuccessful, direct fluorine-18 labelling at the
N
-terminus modified with 6-nitronicotinate afforded a 47.6% radiochemical yield of [
18
F]FNic-MG11. Unfortunately, [
18
F]FNic-MG11
4
was chemically unstable, decomposing slowly through defluorination, thereby impeding any further work with this radiotracer.