Applications of Click Chemistry in Radiopharmaceutical Development

Abstract

Click chemistry, a concept that employs only practical and reliable transformations for compound synthesis, has made a significant impact in several areas of chemistry, including material sciences and drug discovery. The present article describes the use of click chemistry for the development of radiopharmaceuticals. Target templated in situ click chemistry was used for lead generation. The 1,2,3-triazole moiety was found to improve the pharmacokinetic properties of certain radiopharmaceuticals. The reliable Cu(i)-catalyzed click reaction was employed for radiolabeling of peptidic compounds without the need for protecting groups. In summary, the click chemistry approach for the discovery, optimization and labeling of new radiotracers, represents a very powerful tool for radiopharmaceutical development.

Preclinical evaluation and validation of [ 18 F]HX4, a promising hypoxia marker for PET imaging

“…This is, however, not surprising, because the highest [ 18 F]HX4 uptake was found in the urinary bladder, confirming excretion primarily through the kidneys. To reduce bladder and kidney dose, patients should therefore be encouraged to maintain adequate hydration and void frequently (15,16).…”

“…It represents a novel, click chemistry-based generation of derivatives in which structure-activity relationships, focused on the incorporation of a 1,2,3-triazole moiety, have been used to design an agent with preferred pharmacokinetic and clearance properties (15). Biodistribution and dosimetry studies in healthy monkeys and humans showed that the amount of unmetabolized [ 18 F]HX4 in blood and urine samples remained stable, liver and gastrointestinal tract uptake was relatively low, and the highest uptake of [ 18 F]HX4 was found in the urinary bladder, indicating an excretion primarily through the kidneys (15,16). Because of the better water solubility and faster clearance, we hypothesized that 18 F activity, as previously shown (11).…”

Biodistribution and Radiation Dosimetry of the Integrin Marker 18F-RGD-K5 Determined from Whole-Body PET/CT in Monkeys and Humans

“…This tracer binds selectively to integrin a v b 3 (dissociation constant 5 7.9 nM) over other related integrins. The tracer has preferential tumor uptake in U87MG xenografts, with a tumor-to-muscle ratio of more than 5:1 after 2 h, making 18 F-RGD-K5 a promising tracer for imaging integrin a v b 3 expression in vivo in tumors undergoing aberrant angiogenesis (7). In comparison to 18 F-galacto-RGD, the preparation of 18 F-RGD-K5 is simple and straightforward using click chemistry, consisting of a single reaction that can be readily automated (7).…”

Initial Experience of Monitoring Response of Breast Cancer to Bevacizumab-containing Chemotherapy using A New Integrin Specific PET Imaging Tracer [F-18]RGD-K5

“…In a study by Beer et al in 19 patients with solid tumor, the uptake measured by [18F]Galacto-RGD was shown to be highly correlated with immunohistochemical staining expression using α v β 3 -specific antibody LM609, and the uptake was also highly correlated with microvessel density [20]. A structurally related analog, [F-18]RGD-K5, was identified as a promising PET imaging agent for detecting integrin α v β 3 expression in vivo [21]. This tracer contains the well-established integrin α v β 3 -binding motif (an "R-G-D" cyclic peptide) with the addition of a polar, yet metabolically stable, 1,2,3-antitriazole moiety, which biases excretion through the kidneys and into the bladder.…”