Spirocyclic Iodonium Ylide (SCIDY) Technology for 18F-Labeling of Pharmaceuticals and Imaging Agents

Abstract

a site-specific, one-step direct labeling method that introduces fluorine-18 into drug/tracer molecules in high efficiency under metal free conditions. The radiopharmaceutical that synthesized via spirocyclic iodonium ylide (SCIDY) technology has been validated for human use. We are open for licensing opportunities!

Background

Fluorine-18 (18F; t½ = 109.7 min) labelled compounds and radiopharmaceuticals are the mainstay of functional molecular imaging by positron emission tomography (PET) for a broad range of applications including clinical diagnosis and drug discovery. Consequently, there is a rapidly growing demand for new 18F-labeled agents to probe biological processes and targets in vivo by PET. Fluorine-18 is most readily prepared in high specific activity as no-carrier-added [18F]fluoride ion, by proton irradiation of [18O]H2O (18O(p,n)18F nuclear reaction) in low energy (10-16 MeV) medical cyclotrons. Most 18F-labeling methodologies for aromatic nucleophilic substitution (SNAr) reactions employ “naked” [18F]fluoride ion with appropriately activated (electron-deficient) aromatic / heteroaromatic substrates or electrophilic aromatic substitution reactions with [18F]F2 and related reagents derived from elemental fluorine. However, radiofluorination of non-activated arenes from "naked" [18F]fluoride ion represents a major challenge in the field and there is an urgent need for a general and practical methodology that can introduce 18F into molecules which cannot be (easily) achieved using a conventional aromatic nucleophilic substitution (SNAr) reaction or a low-specific-activity [18F]F2 gas method. 

Our innovative work: spirocyclic iodonium ylide (SCIDY) precursors for radiofluorination

In 2014, we discovered a new method that is capable of regioselectively introducing 18F-fluoride ion into non-activated aromatic rings with very wide substrate scope under absolute metal-free conditions. We reported a novel spirocyclopentyl hypervalent iodine(III)-mediated radiofluorination strategy, based on iodonium ylides to afford 18F-aryl fluorides from “naked” [18F]fluoride in high radiochemical yields. The technique involves stable, easily purified precursors and is readily implemented with standard workup procedures and no metal was utilized during the preparation and radiosynthesis. The conceptual advantages of excellent regioselectivity and viability of incorporation of 18F into a wide array of non-activated (hetero)arenes makes this methodology suitable for routine radiopharmaceutical production. 

 

HIT

 

 

 

Applications and Translation

application_and_translation_first_half.png

application_and_translation_second_half.png

 

References

1. Rotstein, B. H.; Stephenson, N. A.; Vasdev, N.; Liang, S. H. "Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics" Nat. Commun. 2014, 5, 4365. Highlighted on Nat Commun as "action shot"; Selected by Chemical and Engineering News for "patentpicks" on October 26, 2015

2. Stephenson, N. A.; Holland, J. P.; Kassenbrock, A.; Yokell, D. L.; Livni, E.; Liang, S. H.; Vasdev, N. "Iodonium Ylide–Mediated Radiofluorination of 18F-FPEB and Validation for Human Use" J. Nucl. Med. 2015, 56, 489-92.

3. Calderwood, S.; Collier, T. L.; Gouverneur, V.; Liang, S. H.; Vasdev, N. "Synthesis of 18F-Arenes from Spirocyclic Iodonium(III) Ylides via Continuous-Flow Microfluidics" J. Fluorine Chem. 2015, 178, 249-253.

4. Wang, L.; Jacobsen, O.; Avdic, D.; Rotstein, B. H.; Weiss, I. D.; Collier, L.; Chen, X.; Vasdev, N.; Liang, S. H. "Ortho-stabilized 18F-azido click agents and application in PET imaging of single-stranded DNA aptamer." Angew. Chem. Int. Ed.  2015, 54, 12777-81; Highlighted on "Atlas of Science" website on October 19, 2015

5. Jacobson, O.; Weiss, I.; Wang, L.; Wang, Z.; Yang, X.; Dewhurst, A.; Ma, Y.; Zhu, G.; Niu, G.; Kiesewetter, D. O.; Vasdev, N.; Liang, S. H.; Chen, X. "18F-labeled Single-Stranded DNA Aptamer for PET Imaging of Protein Tyrosine Kinase-7 Expression" J. Nucl. Med. 2015, 56, 1780-5.

6. Rotstein, B. H.; Wang, L.; Liu, R. Y.; Patteson, J.; Kwan, E. E.; Vasdev, N. & Liang, S. H. "Mechanistic Studies and Radiofluorination of Structurally Diverse Pharmaceuticals with Spirocyclic Iodonium(III) Ylides." Chem. Sci. 2016, 7, 4407-4417.

7. Yuan, G.;  Jones, G. B.; Vasdev, N. & Liang, S. H.   "Radiosynthesis and preliminary PET evaluation of 18F-labeled 2-(1-(3-fluorophenyl)-2-oxo-5-(pyrimidin-2-yl)-1, 2-dihydropyridin-3-yl)benzonitrile for imaging AMPA receptors" Bioorg. Med. Chem. Lett. 2016, 26, 4857-4860.

8. Collier, T. L.; Normandin, M. D.; Stephenson, N. A.; Livni, E.; Liang, S. H.; Wooten, D. W.; Esfahani, S. A.; Stabin, M. G.; Mahmood, U.; Chen, J.; Wang, W.; Maresca, K.; Waterhouse, R. N.; El Fakhri, G.; Richardson, P. & Vasdev, N. "Synthesis and preliminary PET imaging of 11C and 18F isotopologues of the ROS1/ALK inhibitor lorlatinib" Nat. Commun. 2017, 8, article number 15761.

9. Wang, L.; Cheng, R.; Fujinaga, M.; Yang, J.; Zhang, Y.; Hatori, A.; Kumata, K.; Yang, J.; Vasdev, N.; Du, Y.; Ran, C.; Zhang, M-R. & Liang, S. H.  "A Facile Radiolabeling of [18F]FDPA via Spirocyclic Iodonium Ylides: Preliminary PET Imaging Studies in Preclinical Models of Neuroinflammation" J. Med. Chem. 2017, 60, 5222-5227. 

molecule_gallery.pdf682 KB