Preparation of ¹¹C-Carbonyl Compounds and Radiotracer Validation for Cardiac PET Imaging

Abstract

Molecular imaging techniques serve an integral role in clinical practice for the diagnosis and prognosis of various morbidities. Positron emission tomography (PET) is an imaging modality employing radiolabelled probes to visualize biochemical processes. Radiochemical synthesis is used to incorporate radioactive isotopes into small molecules or peptides targeting a protein of interest. Access to radiotracers is therefore dependent on the availability of radiochemical methods for the addition of radionuclides. This thesis describes the key steps in the process of developing a new radiotracer, from designing methodologies for their synthesis, to the production and evaluation of a novel probe, and finally the analysis of tracer kinetics in PET imaging. Beginning with Chapter 1, PET and radiochemistry will be introduced. Chapter 2 is focused on a general methodology to access ¹¹C-amides, using transition metal-catalyzed additions of organozinc iodides to ¹¹C-isocyanates. In the chapter’s central article, [¹¹C]CO₂ produced directly from the cyclotron was captured and converted to reactive ¹¹C-isocyanate electrophiles before being derivatized by aryl and alkyl organozinc iodides. Additional work on the development of alternative ¹¹C-carbonyl compounds is also described. Chapter 3 presents the radiolabelling of one such ¹¹C-carbonyl, describing the development of a radiotracer based on the selective Rev-erb inhibitor SR9009. Given recently elucidated potential for therapeutic applications of Rev-erb inhibitors like SR9009 in the management of cardiovascular disease, (R)- and (S)-[¹¹C]SR9009 were synthesized for cardiac investigation of circadian biology. Chapter 4 explores a novel approach to prepare ¹¹C-amino acids with [¹¹C]CO₂ via carbon isotope exchange. In this chapter, α-amino acids are condensed to Schiff bases using aldehydes; this intermediate can then undergo a carboxylation/decarboxylation cycle in which isotopically-labelled carbon (¹¹C, ¹³C, ¹⁴C) is incorporated. The key paper details the optimization of carbon-11 labelling to prepare enantiopure L- and D-¹¹C-amino acids for imaging. Chapter 5 discusses the pharmacokinetic and metabolic evaluation of [¹⁸F]flubrobenguane (FBBG) in clinical imaging populations to determine radiotracer kinetics. Patients underwent FBBG PET scans to evaluate cardiac denervation. Blood samples were collected and processed to derive vital parameters for image analysis and interpretation. Patient cohorts were statistically compared to evaluate disease-specific differences in the pharmacokinetics of FBBG.