Development of radiolabeled fatty acid derivatives for imaging cardiac metabolism using PET and SPECT

Al-Ali, Zainab Shakir Abdullah

Abstract

Cardiac diseases are the leading cause of death worldwide. To address this problem, a better understanding of biochemical reasons underlying heart pathologies is needed. Fatty acid oxidation (FAO) plays a significant role in cardiac energy production and is therefore an important biomarker for heart disease. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are useful methods to quantify and qualify cardiac metabolic changes during either establishment of disease or therapeutic intervention. The extent of fatty acid oxidation can be visualised using radiolabeled thia-fatty acids. However, the uptake of these tracers as revealed by imaging also depends on their transport into cardiac cell mitochondria and general pharmacokinetics.

In this work, the synthesis of four types of 4-thia fatty acids, 4-thiacaprylic acid/caprylate derivatives (TCD1), 4-thiacapric acid/caprate derivatives (TCD2), 4- thiapalmitic acid/palmitate derivatives (TPD) and 4-thiaoleic acid/oleate derivatives (TOD) is described.

Fluorine-18 radiolabeling for the caprate, palmitate and oleate derivatives was optimised. The decay corrected radiochemical yields for the radiotracers, [18F]FTC2, [18F]FTP and [18F]FTO are 16.15 ± 2.60%, 18 ± 1.20% and 17.70 ± 1.70% respectively. [18F]FTP, [18F]FTO and [18F]FTC2 were found to be stable in serum after 3h at 37°C. PET imaging experiments in rats showed significant cardiac uptake for [18F]FTP and [18F]FTO but not for [18F]FTC2.

A thia-fatty acid delivery method to increase cardiac cell uptake was investigated, based on their coordination to mitochondria targeted transition metal complexes. The cross-bridged cyclam precursor compounds were produced in good yields and novel copper(II) cross-bridged cyclam complexes with a triphenylphosphonium moiety for mitochondria targeting were synthesised. Coordination of radiolabeled thiacapric acid to the complexes was attempted.

Novel 99mTc radiolabeled long chain thia-fatty acids (palmitic and oleic acids) were investigated as potential new radiopharmaceuticals for use in fatty acid oxidation imaging, which would be metabolised by β-oxidation. The intermediate derivatives were synthesised in good yields and fully characterised to obtain the precursors for radiolabeling and to provide reference compounds. 99mTc radiolabeled TACN –thia palmitic and thiaoleic acid were produced.

Citation

Al-Ali, Z. S. A. Development of radiolabeled fatty acid derivatives for imaging cardiac metabolism using PET and SPECT. (Thesis). University of Hull. https://hull-repository.worktribe.com/output/4223957

• Thesis Type: Thesis
• Deposit Date: Feb 21, 2022
• Publicly Available Date: Feb 24, 2023
• Keywords: Chemistry
• Public URL: https://hull-repository.worktribe.com/output/4223957
• Additional Information: Department of Chemistry, The University of Hull
• Award Date: Apr 1, 2018