03/19/2025
By Suzanne Young
The University of Massachusetts Lowell, Department of Chemistry, invites you to attend a Master’s Thesis defense by Madelyn Hallisey on “Novel PET Radiochemistry: Adapting Analytical and Semi-Preparative High Performance Liquid Chromatography Methods to Enhance the Synthesis of the Carbon-11 Radiotracer FLB457.”
Date: Thursday, April 3
Time: 8:30 - 9:30 a.m.
Location: Olney Hall 520
Advisor: Olof Ramstrom, Ph.D., Chemistry, UMass Lowell
External Mentor: Joseph Downey, Ph.D, Instructor in Radiology, Athinoula A. Martinos Center for Biomedical Imaging and Harvard Medical School
Committee Members*
Suzanne Young, Ph.D, Chemistry, UMass Lowell
Erin Bertelsen, Ph.D, Physics and Applied Physics, UMass Lowell
Abstract
Positron emission tomography (PET) is an imaging technique that provides highly detailed images of organs and tissues. To obtain these images, a small amount of radioactive tracer is injected into rodents, non-human primates, or humans. A radioactive tracer, or radiotracer, is a drug compound that has undergone a chemical reaction with a radioactive isotope. [11C]FLB457 is a carbon-11 labeled radiotracer that is used to image dopamine D2 and D3 receptors found in the striatum of the brain. Adaptation of [11C]FLB457 synthesis was last presented in 1995. Since then, technological advancements allow for synthesis improvement without compromising imaging results. In the past, [11C]FLB457 has been synthesized using [11C]methyl iodide ([11C]MeI) with solvents including dimethyl sulfoxide (DMSO) and sodium hydroxide (NaOH).1 Challenges faced with using this method with current technological advancements showed a decrease in amount of radioactivity available upon injection. The overall goal of this project was to develop an improved method of synthesizing [11C]FLB457 including updated chemistry, purification, and quality control analysis methods with a focus on GMP compliance for investigational new drug (IND) submission.
To achieve the goals mentioned, the first step was to develop high performance liquid chromatography (HPLC) methods for purification and quality control analysis. Development began following pre-established methods but yielded problems involving peak tailing and asymmetrical peak shape. To combat these challenges, basic mobile phases were used with HPLC columns that could withstand basic pHs. An analytical method used for quality control analysis was developed that showed repeatable results with a short method time to allow for confirmation of [11C]FLB457 chemical identity and radiochemical purity. A semi-preparative method was developed using the same model of a basic mobile phase to allow for fast purification of the product while removing excess precursor and undesirable materials.
Once analytical and semi-preparative HPLC methods had been developed, experimentation began on adapting the chemical synthesis of [11C]FLB457 both manually and through automation. Similar conditions were explored first to determine a baseline of potential yield capability. Using both manual and automated synthesis methods, similar conditions using [11C]MeI, dimethylformamide (DMF), and tetrabutylammonium hydroxide (TBAOH) and [11C]MeI, DMSO, and TBAOH yielded less than 10 millicuries (mCi) of final dose activity. Due to the less than desirable yield of the final dose, additional methods were explored using [11C]methyl trifluoromethanesulfonate (MeOTf), methyl ethyl ketone (MEK), and TBAOH. It was determined that automated synthesis and purification with [11C]MeOTf, MEK, and TBAOH gave average yields of 62.4 mCi with an average radiochemical purity of 91%.