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Structural studies on radiopharmaceutical DOTA-minigastrin analogue (CP04) complexes and their interaction with CCK2

Piotr F J Lipiński1, Piotr Garnuszek2, Michał Maurin2

  • 1Neuropeptides Department, Mossakowski Medical Research Centre Polish Academy of Sciences, Pawińskiego 5 Str., 02-106, Warszawa, Poland. plipinski@imdik.pan.pl.

EJNMMI Research
|April 18, 2018
PubMed
Abstract

Insights

The minigastrin analogue CP04 shows similar binding affinity for the cholecystokinin receptor subtype 2 (CCK-2R) regardless of the radiometal used, supporting its use in theranostic applications for cancers like medullary thyroid carcinoma.

Area of Science:

  • Radiopharmaceutical chemistry
  • Molecular imaging
  • Cancer theranostics

Background:

  • The cholecystokinin receptor subtype 2 (CCK-2R) is overexpressed in certain cancers, notably medullary thyroid carcinoma (MTC), making it a key target for diagnostic imaging and targeted radionuclide therapy (TRNT).
  • Minigastrin analogue CP04 (DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) is a promising radiopharmaceutical candidate for MTC theranostics.

Purpose of the Study:

  • To evaluate the influence of different radiometals on the binding affinity of CP04 to CCK-2R.
  • To elucidate the binding mode of CP04 to CCK-2R through molecular modeling.

Main Methods:

  • In vitro binding affinity and cellular uptake studies using CP04 complexed with Gallium-68 ([68Ga]Ga3+) and Lutetium-177 ([177Lu]Lu3+).
  • Homology modeling and molecular docking to predict the binding structure of CP04 with CCK-2R.

Main Results:

  • CP04 exhibited comparable CCK-2R binding affinity and cellular uptake when complexed with either [68Ga]Ga3+ or [177Lu]Lu3+.
  • Molecular modeling revealed that the C-terminal of CP04 binds within the CCK-2R cavity, while the N-terminus with the radiometal remains exposed at the solvent-accessible outlet.
  • Radiometal complexation minimally affects the overall conformation of CP04, except in the immediate vicinity of the DOTA chelator.

Conclusions:

  • The binding affinity of CP04 to CCK-2R is relatively insensitive to the choice of radiometal, consistent with structure-activity relationship studies.
  • The proposed binding model supports the theranostic potential of CP04 for CCK-2R-expressing tumors.
  • The model aligns with existing structure-activity relationship data and partially explains site-directed mutagenesis findings.
Keywords:
Cholecystokinin receptor subtype 2Medullary thyroid carcinomaMinigastrin analogueMolecular docking

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