¹⁸F-Labeling Using Click Cycloadditions

Table 3

New developments in ¹⁸F-click [3+2]cycloadditions, showing the 1,3-dipolar ¹⁸F-prosthetic groups, reaction type, and conditions.

^18F-prosthetic group	Steps/reaction time	RCY	Reacting agent	Reaction type/; catalytic system	Overall reaction time^1; (CCA)	RCY; CCA	Literature
C-(4-[^18F]fluoro-phenyl)-N-phenyl-nitrone	2 steps/20 min, (labeling of [^18F]FB-CHO: 1 step, 50 min)	22–37%^1; ([^18F]FB-CHO: 30–50%); (^18F-nitrone: 74%)	Various maleimides		80 min; (10 min)	87–91%	[19]
4-[^18F]fluoro-benzonitrile oxide	3 steps/20 min (labeling of [^18F]FB-CHO: 1 step, 50 min)	28–46%^1; ([^18F]FB-CHO: 30–50%); (^18F-nitro oxide: 92%)	Various dipolarophiles	1,3-dipolar [3+2]cycloaddition, no catalyst	80 min; (10 min)	36–99%	[20]
			Cyclononyne-indomethacins; (COX-2 inhibitor)			81%
			Maleimide-indomethacins; (COX-2 inhibitor)			55%
			Propyne-indomethacins; (COX-2 inhibitor)			35%
N-hydroxy-4-[^18F]fluorobenz-imidoyl chloride	4 steps/20 min (labeling of [^18F]FB-CHO: 1 step, 50 min)	27–45%^1; ([^18F]FB-CHO: 30–50%); (^18F-nitro oxide: 92%); (^18F-benzimidoyl Cl: 99%)	Cyclononyne-𝛽-Ala-Phe-OMe; (dipeptide)		85 min; (10 min)	88%^2
			Norbornene-𝛽-Ala-Phe-OMe; (dipeptide)			82%^2
C-(4-[^18F]fluoro-phenyl)-N-phenyl-nitrone	2 steps/20 min, (labeling of [^18F]FB-CHO: 1 step, 50 min)	22–37%^1; ([^18F]FB-CHO: 30–50%); (^18F-nitrone: 74%)	Terminal alkynes; methyl propiolate	radio-Kinugasa, CuSO4, AscONa; (L-histidine)	80 min; (10 min)	89%; (trans/cis = 2 : 3)	[21]
			Terminal alkyne; propargyl alcohol	radio-Kinugasa, CuI (Cu^I-stabilizing ligands or pyridine)	100 min; (30 min)	82%; (trans/cis = 1 : 5); 60%; (trans/cis = 1 : 5)
			Terminal alkyne; 1-propargyl uracyl; (nucleobase chimera)			65%; (trans/cis = 4 : 1)
			propiolyl-𝛽-Ala-Phe-OMe; (dipeptide)	radio-Kinugasa, CuSO4, AscONa; (L-histidine)	80 min; (10 min)	85%; (trans/cis = 1 : 3)
			propiolated protein; (BSA)			32%
o-/p-[^18F]fluoro-phenyl acetylene	n.d.	n.d.	3,6-dihydro-2H-1,4-oxazine-4-oxide	radio-Kinugasa, CuI (1,10-phenanthroline)	(10 min)	52% (ortho); 41% (para)

1Calculated as sum from all steps.
2Best RCY, obtained only with high precursor amounts.
FB-CHO: 4-fluorobenzaldehyde; CCA: click cycloaddition; PHA: N-phenylhydroxylamine; AscONa: sodium ascorbate’; BSA: bovine serum albumin; n.d.: no data.