A Computational Study of 68Ga-Dota-Ethambutol Synthesis : The Reaction Mechanism Catalyzed by Boric Acid using Hybrid meta-GGA DFT Functional and Diffuse-Polarized Basis Sets Badra Sanditya Rattyananda (1,3,*) Muhamad Abdulkadir Martoprawiro (2) Duyeh Setiawan (3) and Suci Zulaikha Hildayani (4)
1. Master Program of Chemistry, Faculty of Mathematics and Natural Sciences, Bandung Institute of Technology
2. Physical Chemistry Group,Department of Chemistry, Faculty of Mathematics and Natural Sciences, Bandung Institute of Technology
3. National Research & Innovation Agency of Indonesia
4. Doctoral Program of Chemistry, Faculty of Mathematics and Natural Sciences, Bandung Institute of Technology
* Corresponding author, phone/WA: +6285218544675, email: badra.sanditya.rattyananda[at]brin.go.id
Abstract
Indonesia was a country with the most tuberculosis cases in Southeast Asia. For some special cases in patients with low immunity TB bacteria was found to have spread to the bones and brain called tuberculous meningitis. It Diagnosis was difficult using conventional methods thus BATAN has developed a gamma ray-based radiopharmaceutical for diagnosing tuberculous meningitis named 99mTc-Ethambutol. The gamma-ray radiopharmaceuticals has problems in resolution of imaging and Increasing it can be done by changing the radioisotope to a positron-based radioisotope, one of them was Gallium-68. 68Ga-DOTA-Ethambutol was a candidate positron-based compound to improve the diagnostic imaging results of Tuberculous meningitis. The computation study simulated using Orca 5.0.3, Geometry optimization calculation using the medium functional B3LYP and def2-SVP basis set to reduce computational cost, followed by frequency energy using the hybrid meta-GGA functional M06-2X and cc-PVTZ basis set. The reaction has 3 stages of reaction, namely deprotonation, nucleophilic attack and the release of leaving group. The Transition state of its reaction mechanism calculated used M06-2X and diffuse-polarized basis set def2-SVPD that obtained activation energy required for deprotonation was 152.86 kJ/mol, 216.73 kJ/mol for nucleophilic attack and 44.55 kJ/mol for leaving group release. The synthesis became under Exothermic reaction with heat release -57.06 kJ/mol and classified as spontaneous reaction with Gibbs free energy found -39.16 kJ/mol. The rate-determining step identified at the nucleophilic attack reaction which has the largest energy barrier. The quantum computational expect can reduce the time and cost of radiopharmaceutical research which was very large. Furthermore, it was necessary to due molecular docking and dynamic studies to explain the suitability interaction between 68Ga-DOTA-Ethambutol and TB receptors. The predicted properties also can be used as a guide in laboratorium.
Keywords: 68Ga-DOTA-Ethambutol, Radiopharmaceutical, Reaction Mechanism, M06-2X, def2-SVPD, Transition state
