Calcium (Ca2+) is vital to many biological systems, and it contributes to a variety of processes across different organisms, such as aiding the regulation of ossification. Therefore, it is crucial to study the mechanisms of how Ca2+ concentrations are monitored in living cells. Measurements of Ca2+ concentration are completed through the calcium-sensing receptor (CaSR). CaSR is a part of the family C of G protein-coupled receptors (GPCRs). CaSR is found in several biological forms and plays a crucial role in the functionality of organisms. Abnormalities in CaSR are related to severe diseases, such as autosomal dominant hypocalcemia, so it is essential to gain as much knowledge as possible about this receptor. CaSR regulates the intracellular Ca2+ concentration by reacting to extracellular stimuli. It is stimulated by the concentration of divalent cations (Ca2+ and Mg2+) and amino acids. Even small changes in the concentration of metal ions can cause large conformational changes resulting in the activation of CaSR. Amino acids can also modulate the functionality of the receptor, usually by acting as co-agonists. A tryptophan derivative, L-1,2,3,4-tetrahydronorharman-3-carboxylic acid (TNCA), can bind to the extracellular domain of CaSR and act as an agonist when paired with metal ions. The project's primary goal is to synthesize TNCA derivatives to create positron emission tomography (PET) imaging agents to visualize different CaSR disorders and synthesize drugs as treatment options. Halogenated TNCA derivatives have been synthesized in a 55% yield through a three-step procedure. The agonistic potential of these derivatives has been investigated in cell-based studies. Our results suggest that fluorinated TNCA has a higher agonistic potential than the parent compound.

Investigation of CaSR agonists and potential PET agents using halogenated TNCA derivatives

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ACS Fall 2022

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