Copper-Mediated Late-stage Radiofluorination: Five Years of Impact on Pre-clinical and Clinical PET Imaging

Abstract

Purpose: Copper-mediated radiofluorination (CMRF) is emerging as the method of choice for the formation of aromatic C-¹⁸F bonds. This minireview examines proof-of-concept, pre-clinical, and in-human imaging studies of new and established imaging agents containing aromatic C-¹⁸F bonds synthesized with CMRF. An exhaustive discussion of CMRF methods is not provided, although key developments that have enabled or improved upon the syntheses of fluorine-18 imaging agents are discussed.

Methods: A comprehensive literature search from April 2014 onwards of the Web of Science and PubMed library databases was performed to find reports that utilize CMRF for the synthesis of fluorine-18 radiopharmaceuticals, and these represent the primary body of research discussed in this minireview. Select conference proceedings, previous reports describing alternative methods for the synthesis of imaging agents, and preceding fluorine-19 methodologies have also been included for discussion.

Conclusions: CMRF has significantly expanded the chemical space that is accessible to fluorine-18 radiolabeling with production methods that can meet the regulatory requirements for use in Nuclear Medicine. Furthermore, it has enabled novel and improved syntheses of radiopharmaceuticals and facilitated subsequent PET imaging studies. The rapid adoption of CMRF will undoubtedly continue to simplify the production of imaging agents and inspire the development of new radiofluorination methodologies.

Keywords: Copper; Fluorine-18; Positron Emission Tomography; Radiofluorination; Radioligand; Radiotracer.

Figure 1:

[¹⁸F]Fluorodeoxyglucose.

Scheme 1:

Synthesis of [a] Protected 4-[¹⁸F]l-PhA and [b] Protected 6-[¹⁸F]Fluoro-L-DOPA.

Scheme 2:

[a]: Synthesis of 4-[¹⁸F]l-Phe [b]: Synthesis of 6-[¹⁸F]DP [c]:Synthesis and preclinical evaluation of [¹⁸F]DAA1106. Images were obtained six days after anterior cerebral artery occlusion, with the ischemic lesion in the anterior cingulate cortex visible as hyperintensity (white arrowheads). The peri-infarct zone is highlighted by red circles. PET-MR images republished from reference 70 with permission from John Wiley & Sons.

Scheme 3:

Radiosynthesis of fluorine-18 labeled phenylalanine derivatives. [b] PET images of 2- and 4-[¹⁸F]Phe in healthy rat brains. Significant skull accumulation in the latter can be observed. PET images republished from reference 72 with permission from Thieme.

Scheme 4:

Radiosynthesis of [a]: [¹⁸F]FIBG and [b]: indazole 22.

Scheme 5:

ortho-Directed radiofluorination of aryl halides.

Scheme 6:

Seminal reports on the CMRF of organoborons.

Scheme 7:

Ni-catalyzed fluorodeborylation and Cu-mediated radiofluorination sequence.

Scheme 8:

Derisked CMRF of organoborons. Multi-step labeling strategies (not shown) were used for the radiosynthesis of 34–38b.

Scheme 9:

Enhanced CMRF of organoborons for the synthesis of imaging agents. a RCY Reported From Protected Precursor Over Two (Radiofluorination and Deprotection) Steps. Product Obtained Following Deprotection with HI.

Scheme 10:

Synthesis of radiotracers via alcohol-promoted CMRF. [b] Pre-clinical evaluation of 7-[¹⁸F]Trp and corresponding radioisomers, displaying regional-time activity curves for uptake of 7-[¹⁸F]Trp in the skull (blue), pineal gland (red), and dorsal raphe (green) of rats (below). Metabolic stability data republished from Reference 88 with Permission from the ACS.

Scheme 11:

Effects of eluting with pyridine derivatives on CMRF.

Scheme 12:

Radiochemical syntheses with preclinical and in-human evaluations of [¹⁸F]TRACK. [a] In vivo imaging is displayed at high and low effective specific activity in NHP brain [b] Summed PET/MR SUV images at 0–10 min in a healthy human brain. PET images republished from references 93 and with permission from the ACS.

Scheme 13:

Radiosyntheses of [¹⁸F]Tryptphan derivatives. [a]: Synthesis of 5-[¹⁸F]AMT and Decay-corrected rodent PET-CT images of B16F10 melanoma after a 30 min injection of 5-[¹⁸F]AMT. PET-CT images republished from reference 95 with permission from Ivyspring; [b]: Synthesis of 5-[¹⁸F]Trp.

Scheme 14:

Radiosynthesis and preclinical evaluation of 64 and 66. [a]: Biodistribution of 64 in the low activity organs of mice. [b]: PET-CT images of mice bearing LNCaP prostate cancer xenografts. Blocking was performed using non-radioactive CJ-042794. Biodistribution data and PET-CT images republished from references 96 and with permission from Taylor & Francis (open access) and Elsevier, respectively.

Scheme 15:

Synthesis of [¹⁸F]Triacoxib. Statistical analysis displaying uptake in a control and with celecoxib as a blocking agent. SUV data republished from reference 98 with permission from the ACS.

Scheme 16:

[a] Radiosynthesis and preclinical evaluation of 71. Western blot study displaying PARP-1 and β-actin levels with/without irradiation in PSN-1 xenografts. [b] Radiosynthesis an preclinical evaluation of 73. PET imaging in PC3 cell lines of immune-deficient mouse. Western blot study and PET image republished from references 99 and with permission from SNMMI and John Wiley & Sons, respectively.

Scheme 17:

[a]: Synthesis and preclinical evaluation of 75. Whole brain accumulation levels with varying quantities of GluN2B antagonist C-P101,606 [b] Synthesis and preclinical evaluation of 77. Brain-time activity curves from PET study in σ1R-KO and wild-type mice. Eliprodil was used for the blockade study. Uptake data republished from references 102 and with permission from SNMMI and the ACS, respectively.

Scheme 18:

Synthesis and preclinical evaluation of [¹⁸F]FTPQ and [¹⁸F]DPA-713. [a]: MicroPET-CT images obtained following injection of ca. 18.5 MBq for 30 min. [b]: TSPO expression 3 and 5 days after intracerebral injection of AdTNF, and 24 h following PBS and IL-4 injection. PET-CT images and TSPO expression data republished from references 104 and with permission from Springer Nature and John Wiley & Sons, respectively.

Scheme 19:

[a] Synthesis and preclinical evaluation of [¹⁸F]DMFC, [ ¹⁸F]FMC. In vitro ARG of AD brain sections labeled with [¹⁸F]DMFC (left) and [¹⁸F]FMC (right), depicting accumulation along the gray matter of the frontal lobe. [b]: Synthesis of [¹⁸F]SDM-8. ARG image republished from reference 108 with permission from Elsevier.

Scheme 20:

Synthesis and preclinical evaluation of 87a and 87b. PET images of a mice brain depicts (a) Total binding (b) Self-blocking (c) Blocking with ZM241385. PET images republished from reference 110 with permission from John Wiley & Sons.

Scheme 21:

[a] Synthesis and preclinical evaluation of [¹⁸F]AZ10419096 in NHP brain. A: MRI images. B: PET SUV baseline experiment. C: PET SUV blocking experiment using AR-A000002 (2.0 mg/kg) [b] Prosthetic group radiosynthesis of 92. MRI and PET images republished from reference 111 with permission from Elsevier.

Scheme 22:

Synthesis and preclinical evaluation of [¹⁸F]darapladib and [¹⁸F]FBnTP. [a]: Ex vivo tracer accumulations. 1: Macroscopic view. 2: 3D PET imaging view. 3: Corresponding orthoslice of planes a and b. [b]: Dynamic PET images of [¹⁸F]FBnTP in a female mouse, depicting myocardial uptake 1 min post-injection. Images republished from references 113 and with permission from the ACS and John Wiley & Sons, respectively.

Scheme 23:

Radiosyntheses and preclinical evaluation of glycomimetic tracers 98 and 100. PET images of the coronal plane at frames between 0 and 120 min. A: Heart, B: Liver, C: Intestine, D: Bladder. Images republished from reference 115 with permission from the ACS.

Scheme 24:

Radiosynthesis and ARG of [¹⁸F]canagliflozin in a human liver. ARG images republished from reference 116 with permission from John Wiley & Sons.

Scheme 25:

Radiosyntheses of other clinically relevant fluorine-18 labelled molecules via CMRF of organoborons.

Scheme 26:

Radiosyntheses of other clinically relevant fluorine-18 labelled molecules via CMRF of organoborons.

Scheme 27:

Radiosyntheses of other clinically relevant fluorine-18 labelled molecules via CMRF of organoborons.

Scheme 28:

CMRF of arylstannanes for the synthesis of clinically relevant imaging agents.

Scheme 29:

[a] [b] Radiosyntheses of [¹⁸F]MPPF and [c] 4-[¹⁸F]Fluorobenzylalcohol.

Scheme 30:

Modified radiofluorodestannylation protocol. a From protected precursor, RCY reported over two (radiofluorination and HBr deprotection) steps

Scheme 31:

[b] Radiosynthesis of ¹⁸F]NS12137 [a], [¹⁸F]-CFT [b] and [¹⁸F]F-DPA [c].

Scheme 32:

Radiosyntheses and preclinical evaluations of [¹⁸F]-SDM-8. Summed PET SUV images in NHP brain depicting baseline and LEV displacement (30 mg/kg) scans (Above) MRI and PET images in a human brain depicting uptake of 85 and [¹¹C]UCB-J (Below) Images republished from references 109 and , with permission from the ACS and SNMMI, respectively.

Scheme 33:

Improved radiosynthesis of 4(4-[¹⁸F]fluorophenyl)piracetam.

Scheme 34:

CMRF of aromatic C-H bonds.

Scheme 35:

C-H radiofluorination using a hypervalent iodine reagent.