Organofluorine Compounds in Fluorine-18 Positron Emission Tomography Imaging

The application of organofluorine compounds is widespread with many current uses in the life sciences and medical field. As modern methods for the introduction of fluorine into molecules continue to develop, so is the growing use of fluorine and its radioisotope, fluorine-18, in the medical field. This mini review summarizes some of the major advancements pertaining to radiotracers for positron emission tomography (PET) imaging and its application as a tool to aid in the diagnosis of Alzheimer’s disease and cancer. Further offered is a brief overview of synthetic methods for preparing organofluorine compounds and rise of organotrifluoroborates in F PET imaging.


Introduction
Organofluorine compounds are abundant in medicine and society-largely by human design and chemical synthesis, not de novo in Nature. In fact, only twenty-one fluorine-containing metabolites among an estimated 130,000 structurally characterized natural products are known [1][2][3]. This is in sharp contrast to 30% of agrochemicals and 20% of pharmaceuticals containing fluorine, including several of the top drugs, e.g., 5-fluorouracil, fluoxetine (Prozac), paroxetine (Paxil), ciprofloxacin (Cipro), mefloquine, and fluconazole [4]. Today, thanks to advancements in chemical synthesis, the incorporation of fluorine into compounds is becoming a simpler task that is enabling innovations in medicine and bio-oriented applications. With this has been major advancements, such as the ever-useful non-invasive positron emission tomography (PET) imaging technique [5,6]. In this regard, the use of unnatural radionuclide fluorine-18 ( 18 F), with a fleeting half-life of 109.8 min/h, has a prominent status in 18 F PET imaging [7][8][9][10][11]. Contributing to this widespread use is the small size (van der Waals radius of 1.47 Å) and high Pauling electronegativity of 3.98 of the fluorine atom, referred to by some as a "small atom with a big ego." What is more, fluorine has the ability to influence molecular conformation and improve metabolic stability, solubility, permeability, and protein binding [12,13]. Meanwhile, 18 F is among one of the safest radioisotope probes owing to minimal radiation exposure upon administration, low-toxicity, and high signal-tonoise ratios [14].
In this short review, we touch upon the synthesis of fluorine-18 labeled organofluorine compounds and discuss select usages in 18 F PET imaging for two widespread diseases, namely cancer and Alzheimer's disease. Additionally, we delve into timely developments While by no means comprehensive, we hope this mini review pro-challenging to implement [15]. Alternatively, nucleophilic aromatic substitution (S N Ar) is a more viable means for preparing various 18 F aryl-containing, metabolically-stable organofluorine compound radiotracers, e.g., [ [16][17][18]. Although some of these strategies for late-stage 18 F incorporation into molecules are not ideal, recent technologies are enabling this reactivity to occur under more mild conditions and fast reaction times, e.g., microwave heating as opposed to conventional heating. Complementing this alternative form of heating is the growing use of diaryliodonium salts, dediazoniation reactions, electrochemical radiofluorination and exploitation of nonhazardous electrophilic fluorine sources, e.g., [ 18 F]Selectfluor [19]. 18 F PET imaging has proven its merit as a diagnostic tool, with its use in helping diagnose two pervasive illnesses, namely Alzheimer's disease and cancer, thus, making them exemplar cases for discussion.

Alzheimer's Disease and 18 F PET Imaging
Turning first to Alzheimer's disease, this neurodegenerative disorder affects approximately 6% of the global population over the age of 65 and accounts for around 80% of all dementia diagnoses, with an associated cost for treatment in excess of $500 billion annually [20][21][22]. Alzheimer's disease is characterized by a combination of neuropathological features, including extracellular brain amyloidosis, intracellular tau accumulation, brain atrophy and cell depletion [23]. As this is a progressive disorder, early-stage identification is of the utmost importance. To date, the majority of PET imaging approaches have targeted amyloid-β aggregates due to its indisputable specific association with Alzheimer's disease [24].
In this context, 18  into clinical practice with promising outcomes. Although these radiotracers have shown remarkable accuracy in amyloid-β detection to assist in diagnosis, they exhibit additional white matter binding, thus, decreasing specificity to amyloid-β [25,26]. While the frontiers of science are clearly being pushed forward with respect to the development of 18 F radiotracers, this is still an imperfect process; there is an obvious need to implement more efficient 18 F radiotracers that manifest in more specific binding to amyloid-β.

Cancer and 18 F PET Imaging
Cancer, as the second leading cause of deaths worldwide, has a major impact on society as attested for by an estimated 9.6 million deaths in 2018. Globally, 1 in 6 deaths results from cancer, and by 2030 the number of new cancer cases per year is expected to rise to 23.6 million. This abnormal, uncontrollable cell growth and proliferation, otherwise known as cancer, has over 227 subtypes. In men, the highest percentages of cancer types occur in the prostate, lung and bronchus, colon and rectum, and urinary bladder, while in women cancer prevalence is highest in the breast, lung and bronchus, colon and rectum, uterine corpus, and thyroid. In contrast, children are most susceptible to cancers that target blood, the brain or lymph nodes [27]. Some conventional methods for monitoring prognosis and treatment of cancer include radiography, ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) [28]. More recently, [ 18 F]fluorodeoxyglucose -positron emission tomography ( 18 F-DG PET) has emerged as an effective tool for characterizing tumors based on biochemical changes at the molecular level [29]. What is more, its use continues to grow with the number of 18 F-DG PET scans performed in the United States alone having increased nearly 9-fold in 2010. Although 18 F-DG is the most commonly employed radiotracer for PET imaging (96% of PET studies in 2011 used 18 F-DG), it has limitations in assessing several relevant tumors, such as prostate cancer [30]. Moreover, 18 F-DG PET scans are limited to simple metrics like maximum standardized uptake value, metabolic tumor volume, or total lesion glycolysis, which have limited predictive value. Therefore, there is a pressing need for the development and clinical application of different PET radiopharmaceuticals [31,32]. To meet this need, several newer agents have been studied in humans, including radiotracers classified by the metabolic processes they target, e.g., ( 18 F-FLT), hypoxia ( 18 F-FMISO), apoptosis ( 18 F-ML-10), protein synthesis ( 18 F-FET), membrane metabolism ( 11 C choline), and tumor-specific agents ( 18 F-FES) [29].

F Labeled Organotrifluoroborates
One significant breakthrough in 18 F PET imaging has been the advancement of 18 F labeled organotrifluoroborate imaging agents (e.g., 18 F containing aryl trifluoroborates) [33,34]. Critical to the use of organotrifluoroborates as imaging agents, however, is chemical stability to hydrolytic defluorination resulting in free fluoride producing unwanted background signals making 18 [35]. In extending ArBF 3 stability further, onium ion stabilized trifluoroborates have been reported, wherein ammonium trifluoroborates were proven effective as in vivo imaging agents [36,37]. As a recent entry, we have reported stability studies and the synthesis of bis(amino)cyclopropenium trifluoroborate (BAC-BF 3 ) adducts having remarkable stabilities toward hydrolysis, and presumable high lipophilic character, making them attractive targets for future 18 F PET imaging applications (Figure 1) [38].
Taken together, these promising qualities provide a strong impetus for the development of new synthetic methods tailored to the design of 18 F radiolabeled organotrifluoroborate molecules for 18 F PET imaging and ongoing research in our group is exploring this aspect.

Figure 1:
A series of BAC-BF 3 compounds reported by Dudding and co-workers with variable substituents bound to the core cyclopropenium ring [38].

Conclusion
In this mini review, coverage of critical aspects relating to the synthesis of organofluorine compounds and application of the 18 F isotope in PET imaging for Alzheimer's disease and cancer was provided. Furthermore, organotrifluoroborates were also highlighted as promising molecules in the context of 18 F labeling that have seen particular growth in recent years. It is our hope this mini review, and the literature citations herein, will influence the future design of organofluorine radiotracers for improving current issues in the medical field.