¹⁸F-Labeling Using Click Cycloadditions

Table 1

Summary of the prosthetic groups, reaction conditions, and reaction partners applied for copper-catalyzed click ¹⁸F-fluorination.

^18F-prosthetic group	Steps/reaction time^1	RCY^2	Reacting agent	Catalytic system	Overall reaction time^1; (CCA)	RCY^2; CCA	Literature
[^18F] fluoroalkynes	1 step, 10 min	36–81%	N-(3-azidopropionyl) peptides	CuI/NaAsc/DIPEA	30 min	54–99%	[26]
4-[^18F]fluoro-1-butyne	1 step, 15 min (estimated)	n.d.	Glucopyranosyl azide		75–80 min	30%	[27]
4-[^18F]Fluoro-1-butyne	1 step, 15 min	45±3%	2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl azide	Cu(I)/Asc/2,6-lutidine	30 min	27±6%	[28]
5-[^18F]fluoro-1-pentyne	1 step, 15 min	59±6%				52±5%
	1 step, 22 min	86±2%	𝛼V𝛽6 specific peptide A20FMDV2 azide	CuI/Asc	66 min	8.7±2.3%	[29]
6-[^18F]fluoro-1-hexyne	1 step, 12 min	70–85%	𝛾-(4-azido-butyl)-folic acid amide	CuI	1.5 h	25–35%	[30]
[^18F] fluoroethyl azide ([^18F] FEA)	1 step, 15 min	55%	Terminal alkynes	Excess of Cu^2+/Asc or copper powder	1 h	61–98% respectively; 15–98% with copper powder	[31]; [32]
		n.d.	Caspase 3/7 Selective Isatin	CuSO4/Asc	n.d.	65±6%	[33]
			RGD peptides	Cu^2+/Asc		47±8%	[34]
			3-Cyanoquinoline core		3 h	37±3.6%	[35]
			Apoptosis marker ICMT11	CuSO4/Asc/BPDS	n.d.	1–3.4% n.d.c.	[36]
			5-Ethynyl-2′-deoxyuridine	CuI/ascorbic acid/DIPEA		75±10%	[37]
			[Tyr^3]octreotate analogues	CuSO4/Asc/BPDS	30 min (estimated)	40–64%	[38]
			ICMT-11 (automated synthesis)		90 min	3±2.6% n.d.c.	[39]
			Nucleosides	CuSO4/Asc	n.d.	8–12% n.d.c.	[40]
			4-(prop-2-ynyloxy)Benzaldehyde		35 min	90%	[41]
			Haloethylsulfoxides	CuI/ascorbate/DIPEA	n.d.	28.5±2.5%	[42]
		50% n.d.c.	Nitroaromatic substrates	CuSO4/Asc	1 h		[43]
		71±4%	RGDfK		60 min	60±2%	[44]
		55%	Alkyne-func.; 6-halopurines	One-pot BPDS-copper(I) (CuSO4/NaAsc.)	1 h	55–75%	[45]
		n.d.	tert-butyl ester of N-Boc-(S)-propargyl glycine	CuSO4, NaAsc	2.5 h	58±4%	[46]
	Precursor: 2 steps; [^18F]FEA: 15 min.	n.d.	3-Butynyl triphenyl phosphonium bromide		1 h	n.d.	[47]
	1 step, 5–10 min	68–75%	Alkynes of benzene rings		30 min	25–87%	[48]
[^18F] FEA from a polyflourinated sulfonate precursor	n.d.	n.d.	FtRGD		70–75 min	10–30% n.d.c.	[49]
^18F-Fluoro-PEG-Alkyne	1 step, 20 min	85–94%	Various azides	CuSO4/Asc	10–30 min	71–99%	[50]
	1 step, 15 min	65±1.9%	E(RGDyK)2 azide		110 min (estimated)	52±8.3%	[51]
		57%	Nanoparticle azide		1 h (estimated)	58%	[52]
[^18F]PEG3-azide	1 step, 40 min	62±4%	N-alkynylated peptide	CuSO4/Asc/BPDS	2 h (estimated)	31±6%	[53]
		n.d.	ZnO nanoparticle alkynes		n.d.	>95%	[54]
[^18F]PEG-azide	Precursor: 2 steps; labeling: 1 step	labeling: 58%	𝛾-(11-azido-3,6,9-trioxaundecanyl)folic acid amide	CuAcetate, NaAsc	2.5 h	8.5%	[55]
4- [^18F]fluoro-N-methyl-N-(prop-2-ynyl)- benzenesulfonamide (p[^18F] F-SA)	Precursor: 3 steps,; labeling: 1 step, 80 min	32±5%	Azide-functionalized neurotensin	Cu(I)-TBTA	n.d.	66%	[56]
			Azide-functionalized human serum albumin (HSA)		100 min	55–60%	[57]
		n.d.	Azide-functionalized phosphopeptide, protein (HAS), oligonucleotide (L-RNA)	CuSO4/Asc	2 h	77%/55–60%/25%	[58]
[^18F] FPy5yne	1 step, 15 min	42%	N3–(CH2)4–CO–YKRI–OH (BG142)	Tetrakis(acetonitrilo) copper(I) hexa fluorophosphates/TBTA	160 min	18.7%	[59]
			Azide-functionalized DNA	CuBr/TBTA and 2,6-lutidine	276 min	24.6±0.5%
2-[^18F]fluoro-3-pent-4-yn-1-yloxypyridine ([^18F]FPyKYNE)	20–25 min	20–35%	Azide-functionalized RGD peptide	CuSO4/Asc	125 min	12–18%	[60]
6-[^18F]fluoro-2-etynylpyridine	1 step, 10 min	27.5±6.6%	D-amino acid analogue of WT-pHLIP azide	Cu-Acetate/NaAsc	85 min	5–20%	[61]
propargyl 4- [^18F]fluorobenzoate ([^18F]PFB)	Precursor: 2 steps,; labeling: 1 steps, 15 min	58±31%	Benzyl azide, two lysine derivatives, transglutaminase-reactive peptide	CuSO4/Asc	1 h (estimated)	88±4%,; 79±33% and 75±5%; 37±31%	[62]
4-[^18F]fluoro-3-nitro-N-2-propyn-1-yl-benzamide; ([^18F] FNPB)	1 step, 40 min	58%	Azido-peptides cRGDfK and D4 peptide		1 h	87–93%	[63]
1-(azidomethyl)-4- [^18F]-fluorobenzene	4 steps, 75 min	34%	4-Ethynyl-𝐿-phenylalanine-peptide	CuI/NaAsc/DIEA	90 min	90%	[64]
	4 steps, 75 min	41%	siRNA alkyne	CuSO4/Asc/TBTA	120 min	15±5%	[65]
	1 step, 45 min	84%	siRNA-linker (two new alkyne-bearing linkers)	CuSO4/Asc	120 min	12%	[66]
1-Azido-4-(3-[^18F] fluoropropoxy)benzene	4 steps, 75 min	35%			120 min	15±5%	[65]
[^18F] (azidomethyl)fluorobenzene	1 step, 94–188 s	around 40%	siRNA alkyne		n.d.	n.d.	[67]
4-[^18F]Fluorophenylazide		around 15%
3,4,6-tri-O-acetyl-2-deoxy-2- [^18F]fluorogluco-pyranosyl azide	1 step, 30 min	71±10%	Fmoc-L-propargylglycine	CuSO4/Asc	1.5 h (estimated)	60%	[68]
	2 step, 7.5 min	n.d.	Alkyne-functionalized peptides (RDG, neurotensin peptoid)		75 min	17–20% n.d.c.	[69]
		52%	folate alkyne	Cu-Acetate/NaAsc	3 h	5–25%	[70]
	1 step, 10 min	84%	RGD-peptide alkyne	CuSO4/Asc	70–75 min	16–24%	[71]
	1 step	1.3–4.7%	Alkyne-bearing protein	CuBr/TTMA	80–100 min	4.1%	[72]
		n.d.	ETAR ligand alkyne	CuSO4/Asc	70 min	20–25% n.d.c.	[73]
			cyanoquinoline (EGFR) alkyne		90 min	8.6±2.3% n.d.c.	[74]
[^18F] 𝐀𝐫𝐁𝐅𝟑^−	1 step, 20 min	n.d.	Alkyne-functionalized RGD	Cu^I/Asc	1 h	n.d.	[75]
			Alkyne-functionalized bombesin (BBN)			20±10% n.d.c.	[76]
	2 steps,		Alkyne-functionalized RGD-boronate		30 min	15–30%	[77]
piperazine-based [^18F] AFP; [^18F] BFP	AFP: 4 steps, 54 h; BFP: 4 steps, 72 h; [^18F]AFP: 1 step, 40 min; [^18F]BFP: 1 step, 40 min	[^18F]AFP: 29±5%; [^18F]BFP: 31±9%	N-Fmoc-e-azido-Lnorleucine (amino acid), SNEW peptide	CuSO4, Asc	2 h	Amino acid: 59–79%; SNEW peptide: 17–25%	[78]
[^18F] serine	2 steps, 125 min	28±5%	cRDG-azide	CuSO4, Asc	145 min	75%	[6]

1Calculated as sum from all steps, for the ¹⁸F-prosthetic group, respectively, for the overall reaction yielding the click product, starting from fluorine-18.
2Radiochemical yields for the ¹⁸F-prosthetic group starting from fluorine-18 for the click reaction, respectively; decay corrected, as long as not noted elsewise.
CCA: click cycloaddition; (n.)d.c.: (not) decay corrected; Asc: ascorbate; DIPEA: diisopropylethylamin; TBTA: tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine; n.d.: no data.