Development of Two Fluorine-18 Labeled Prostate-Specific Membrane Antigen Inhibitors for Positron Emission Tomography Imaging of Prostate Cancer

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Title: Development of Two Fluorine-18 Labeled Prostate-Specific Membrane Antigen Inhibitors for Positron Emission Tomography Imaging of Prostate Cancer
Author: Alanen, Osku
Contributor: University of Helsinki, Faculty of Science, Department of Chemistry
Thesis level: master's thesis
Abstract: Prostate cancer remains one of the most frequently diagnosed cancers in men. While its localized form is typically slowly advancing, the aggressive and metastasized forms are responsible for a significant amount of deaths in men in developed countries. Thus, more reliable methods of diagnosis are currently highly sought-after. Prostate Specific Membrane Antigen (PSMA) remains a highly-researched receptor of choice, which has been found to be overexpressed in majority of prostate cancers. Several PSMA-targeting inhibitors with suitable radioisotopes are already being utilized for PET imaging (18F, 68Ga) and treatment (177Lu) of prostate cancer, with new radiotracers possessing improved characteristics being highly sought-after. Fluoroglycosylation is a typical method of altering the properties of radiotracers, leading into more desirable tracer characteristics, such as increased renal excretion due to the compound’s increased hydrophilicity. This can be achieved with chemical reactions, such as oxime formation, where the molecule is conjugated with a fluorine-containing carbohydrate. The aim of this study was to develop two 18F-labeled PSMA inhibitors via oxime formation by utilizing two 18F-labeled carbohydrates: 5-[18F]fluoro-5-deoxyribose ([18F]9) and 2-[18F]fluoro-2-deoxy-D-glucose ([18F]12). The precursor 3 moiety was successfully synthesized by utilizing an amide coupling reaction (yield 56%), followed by acid-catalyzed deprotection. The purification of precursor 3 was achieved by high-performance liquid chromatography (HPLC) with a yield of 29%. The precursor moiety was conjugated with [18F]9 and [18F]12 via oxime formation to yield compounds [19F]4 (yield 39%) and [19F]5 (yield 39%), respectively. This was followed by the synthesis of their respective radioisotopes, [18F]4 and [18F]5. [18F]9 exhibited more favorable labeling characteristics with precursor 3 compared to those of [18F]12, likely due to its readily-available aldehydic form, and milder reaction conditions. Conjugation of [18F]9 with precursor 3 moiety was successfully achieved in 15 minutes at room temperature in the presence of 0.3 M anilinium acetate buffer, with a radiolabeling yield up to 91% (1.5 mM peptide concentration). Comparably, conjugation with [18F]12 was achieved in 30 minutes at 85 ℃ in the presence of aniline, with a radiolabeling yield of 57% (9.8 mM peptide concentration). Minor by-product formation was also evident with [18F]5 while the reaction appeared more specific with [18F]4. Purification of [18F]4 was achieved by HPLC, yielding the radiotracer with 98% radiochemical purity. Similarly, purification of [18F]5 was demonstrated with HLPC using a smaller batch, yielding the product with a radiochemical purity of 88%. Minor degradation of the oxime ether bond into free [18F]9 or [18F]12 was evident as a function of time in an acidic environment, especially with [18F]5. The lipophilicity of the compounds was also demonstrated by the shake-flask method. Both compounds were found to be highly hydrophilic, with LogD7.4 values of –2.8±0.3 and -3.1±0.2 for [18F]5 and [18F]4, respectively. Further experiments should be made to optimize the radiosynthesis protocols for higher activities, and to determine the minimum peptide concentration and reaction time needed for the oxime ether formation. Additionally, the molar activities of the compounds should be determined. Also, the IC50 inhibition potency of PSMA with [18F]4 should be evaluated prior to any in vivo trials to better evaluate its potential as a possible PSMA inhibitor.
URI: URN:NBN:fi-fe2017121155630
Date: 2017
Discipline: Radiochemistry

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