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Updated: Aug 15, 2026
08:09
15N CPMG Relaxation Dispersion for the Investigation of Protein Conformational Dynamics on the µs-ms Timescale
Published on: April 19, 2021
From 18F‑MC225 to Conformationally Free Derivatives
Anna Teresa Lisi1, Francesco Mastropasqua1, Carmen Abate1
1Departement of Pharmacy-Pharmaceutical Sciences, University of Bari Aldo Moro, Bari 70125, Italy.
ACS Omega
|August 14, 2026
Summary
A new PET radiotracer derivative, 2c, shows higher P-glycoprotein activity than MC225. This development aids in imaging neurodegenerative diseases and antidepressant drug resistance, with potential applications in heart failure research.
Area of Science:
- Neuroscience
- Radiochemistry
- Pharmacology
Background:
- Positron Emission Tomography (PET) radiotracer [18F]-MC225 images P-glycoprotein (P-gp) at the blood-brain barrier (BBB).
- P-gp levels are altered in neurodegenerative diseases (MCI, AD, PD) and antidepressant drug resistance.
- Current PET imaging with [18F]-MC225 shows differential brain uptake correlating with P-gp activity.
Purpose of the Study:
- To synthesize and evaluate novel P-gp imaging agents based on the [18F]-MC225 scaffold.
- To investigate the impact of isosteric substitution on P-gp interaction and imaging properties.
- To identify new radioligands for P-gp imaging in neurological disorders and heart failure.
Main Methods:
- Synthesis of conformationally free derivatives of [18F]-MC225.
- In vitro P-gp activity assays comparing novel compounds with MC225.
- Molecular docking, Root Mean Square Deviation (RMSD), and Rog timeline plot analyses.
- Assessment of lipophilicity (log P) for potential radiolabeling and in vivo applications.
Main Results:
- Aryl-(oxy)-derivative 2c demonstrated significantly higher in vitro P-gp activity than MC225 (EC50 = 1.8 μM vs. 6.35 μM).
- Molecular modeling corroborated the enhanced P-gp binding affinity of compound 2c.
- Compound 2c exhibits lower lipophilicity than MC225, making it suitable for [11C]/[18F] radiolabeling and in vivo imaging.
Conclusions:
- Compound 2c represents a promising P-gp imaging agent with improved in vitro activity.
- The developed compounds offer potential for diagnosing neurodegenerative diseases and monitoring antidepressant drug response.
- The lower lipophilicity of 2c enhances its suitability for PET imaging of P-gp in conditions like heart failure.
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