Abstract
Fluorescent compounds based on synthetic small molecules are powerful tools to visualize biological events in living cells and organisms. Ever since the discovery of organic fluorescent compounds in the late nineteenth century, efforts have been made to “see” the behaviors of specific biomolecules in living systems by using these dyes as labels. Also, following the development of fluorescent Ca2+ indicators in the 1980s, many fluorescent probes or biosensors, which are defined as molecules that show a change in fluorescence properties in the presence of their target molecule, have been reported and applied in biological research. Today, a variety of probes are available that target metal ions, pH, enzyme activities, and signaling molecules. In this review, we first consider the history of organic fluorescent molecules and discuss their utility for labeling biomolecules and staining cells. Then, we review recent progress in small-molecule fluorescent probes for metal ions and reactive oxygen species, focusing on representative work in each category. Finally, we briefly discuss attempts to create novel kinds of probes, including hybrids of small molecules and genetically encoded proteins, with the potential to overcome some of the limitations of current probes.
Similar content being viewed by others
References
Abo M, Urano Y, Hanaoka K, Terai T, Komatsu T, Nagano T (2011) Development of a highly sensitive fluorescence probe for hydrogen peroxide. J Am Chem Soc 133:10629–10637
Ahn Y-H, Lee J-S, Chang Y-T (2007) Combinatorial rosamine library and application to in vivo glutathione probe. J Am Chem Soc 129:4510–4511
Baek NY, Heo CH, Lim CS, Masanta G, Cho BR, Kim HM (2012) A highly sensitive two-photon fluorescent probe for mitochondrial zinc ions in living tissue. Chem Commun 48:4546–4548
Baeyer A (1871) Ueber eine neue Klasse von Farbstoffen. Ber Dtsch Chem Ges 4:555–558
Baker MD, Wood JN (2001) Involvement of Na+ channels in pain pathways. Trends Pharmacol Sci 22:27–31
Ballou B, Ernst LA, Waggoner AS (2005) Fluorescence imaging of tumors in vivo. Curr Med Chem 12:795–805
Baruch A, Jeffery DA, Bogyo M (2004) Enzyme activity—it’s all about image. Trends Cell Biol 14:29–35
Belov VN, Wurm CA, Boyarskiy VP, Jakobs S, Hell SW (2010) Rhodamines NN: a novel class of caged fluorescent dyes. Angew Chem Int Ed 49:3520–3523
Bers DM (2008) Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 70:23–49
Betzig E, Patterson GH, Sougrat R, Lindwasser OW, Olenych S, Bonifacino JS, Davidson MW, Lippincott-Schwartz J, Hess HF (2006) Imaging intracellular fluorescent proteins at nanometer resolution. Science 313:1642–1645
Brancaleon L, Durkin AJ, Tu JH, Menaker G, Fallon GD, Kollias N (2001) In vivo fluorescence spectroscopy of nonmelanoma skin cancer. Photochem Photobiol 73:178–183
Brookner CK, Follen M, Boiko I, Galvan J, Thomsen S, Malpica A, Suzuki S, Lotan R, Richards-Kortum R (2000) Autofluorescence patterns in short-term cultures of normal cervical tissue. Photochem Photobiol 71:730–736
Bünzli J-CG (2010) Lanthanide luminescence for biomedical analyses and imaging. Chem Rev 110:2729–2755
Burdette SC, Walkup GK, Springler B, Tsien RY, Lippard SJ (2001) Fluorescent sensors for Zn2+ based on fluorescein platform: synthesis, properties and intracellular distribution. J Am Chem Soc 123:7831–7841
Burgoyne RD (2007) Neuronal calcium sensor proteins: generating diversity in neuronal Ca2+ signaling. Nat Rev Neurosci 8:182–193
Callan JF, de Silva AP, Magri DC (2005) Luminescent sensors and switches in the early 21st century. Tetrahedron 61:8551–8588
Camakaris J, Voskoboinik I, Mercer JF (1999) Molecular mechanisms of copper homeostasis. Biochem Biophys Res Commun 261:225–232
Ceresole M (1888) Production of new red coloring-matter. US Patent 377,349
Chalfie M, Tu Y, Euskirchen G, Ward WW, Prasherf DC (1994) Green fluorescent protein as a marker for gene expression. Science 263:802–805
Chang MCY, Pralle A, Isacoff EY, Chang CJ (2004) A selective, cell-permeable optical probe for hydrogen peroxide in living cells. J Am Chem Soc 126:15392–15393
Chen X, Conti PS, Moats RA (2004) In vivo near-infrared fluorescence imaging of integrin αvβ3 in brain tumor xenografts. Cancer Res 64:8009–8014
Chen X, Lee K-A, Ha E-M, Lee KM, Seo YY, Choi HK, Kim HN, Kim MJ, Cho C-S, Lee SY, Lee W-J, Yoon J (2011) A specific and sensitive method for detection of hypochlorous acid for the imaging of microbe-induced HOCl production. Chem Commun 47:4373–4375
Chen S, Lu J, Sun C, Ma H (2010) A highly specific ferrocene-based fluorescent probe for hypochlorous acid and its application to cell imaging. Analyst 135:577–582
Chen X, Pradhan T, Wang F, Kim JS, Yoon J (2012) Fluorescent chemosensors based on spiroring-opening of xanthenes and related derivatives. Chem Rev 112:1910–1956
Chen X, Zhong Z, Xu Z, Chen L, Wang Y (2010) 2′,7′-Dichlorodihydrofluorescein as a fluorescent probe for reactive oxygen species measurement: forty years of application and controversy. Free Radic Res 44:587–604
Chudakov DM, Matz MV, Lukyanov S, Lukyanov KA (2010) Fluorescent proteins and their applications in imaging living cells and tissues. Physiol Rev 90:1103–1163
Conley NR, Biteen JS, Moerner WE (2008) Cy3–Cy5 covalent heterodimers for single-molecule photoswitching. J Phys Chem B 112:11878–11880
Coons AH, Creech HJ, Jones RN, Berliner E (1942) The demonstration of pneumococcal antigen in tissues by the use of fluorescent antibody. J Immunol 45:159–170
D’Autréaux B, Toledano MB (2007) ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol 8:813–824
de Silva AP, Gunaratne HQN, Gunnlaugsson T, Huxley AJM, McCoy CP, Rademacher JP, Rice TE (1997) Signaling recognition events with fluorescent sensors and switches. Chem Rev 97:1515–1566
de Silva AP, Rupasinghe RAD (1985) A new class of flurescent pH indicators based on photo-induced electron transfer. J Chem Soc Chem Commun (23):1669–1670
Dodani SC, Domaille DW, Nam CI, Miller EW, Finney LA, Vogt S, Chang CJ (2011) Calcium-dependent copper redistributions in neuronal cells revealed by a fluorescent copper sensor and X-ray fluorescence microscopy. Proc Natl Acad Sci USA 108:5980–5985
Domaille DW, Que EL, Chang CJ (2008) Synthetic fluorescent sensors for studying the cell biology of metals. Nat Chem Biol 4:168–175
Ducibella T, Fissore R (2008) The roles of Ca2+, downstream protein kinases, and oscillatory signaling in regulating fertilization and the activation of development. Dev Biol 315:257–279
Egawa T, Hanaoka K, Koide Y, Ujita S, Takahashi N, Ikegaya Y, Matsuki N, Terai T, Ueno T, Komatsu T, Nagano T (2011) Development of a far-red to near-infrared fluorescence probe for calcium ion and its application to multicolor neuronal imaging. J Am Chem Soc 133:14157–14159
Egawa T, Koide Y, Hanaoka K, Komatsu T, Terai T, Nagano T (2011) Development of a fluorescein analogue, TokyoMagenta, as a novel scaffold for fluorescence probes in red region. Chem Commun 47:4162–4164
Ellinger P (1940) Fluorescence microscope in biology. Biol Rev 15:323–347
Eng J, Lynch RM, Balaban RS (1989) Nicotinamide adenine dinucleotide fluorescence spectroscopy and imaging of isolated cardiac myocytes. Biophys J 55:621–630
Fluhler E, Burnham VG, Loew LM (1985) Spectra, membrane binding, and potentiometric responses of new charge shift probes. Biochem 24:5749–5755
Foemming MK, Sames D (2007) Harnessing functional plasticity of enzymes: a fluorogenic probe for imaging 17α-HSD10 dehydrogenase, an enzyme involved in Alzheimer’s and Parkinson’s diseases. J Am Chem Soc 129:14518–14522
Fölling J, Belov V, Kunetsky R, Medda R, Schönle A, Egner A, Eggeling C, Bossi B, Hell SW (2007) Photochromic rhodamines provide nanoscopy with optical sectioning. Angew Chem Int Ed 46:6266–6270
Förster T (1959) Transfer mechanism of electronic excitation. Discuss Faraday Soc 27:7–17
Frederickson CJ, Kasarskis EJ, Ringo D, Frederickson RE (1987) A quinoline fluorescence method for visualizing and assaying the histochemically reactive zinc (bouton zinc) in the brain. J Neurosci Methods 20:91–103
Gee KR, Brown KA, Chen W-NU, Bishop-Stewart J, Gray D, Johnson I (2000) Chemical and physiological characterization of fluo-4 Ca2+-indicator dyes. Cell Calcium 27:97–106
Gomes A, Fernandes E, Lima JLFC (2005) Fluorescence probes used for detection of reactive oxygen species. J Biochem Biophys Methods 65:45–80
Gomes A, Fernandes E, Lima JLFC (2006) Use of fluorescence probes for detection of reactive nitrogen species: a review. J Fluoresc 16:119–139
Gonçalves MST (2009) Fluorescent labeling of biomolecules with organic probes. Chem Rev 109:190–212
González JE, Tsien RY (1997) Improved indicators of cell membrane potential that use fluorescence resonance energy transfer. Chem Biol 4:269–277
Grinvald A, Fine A, Farber IC, Hildesheim R (1983) Fluorescence monitoring of electrical responses from small neurons and their processes. Biophys J 42:195–198
Grynkiewicz G, Poenie M, Tsien RY (1985) A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 260:3440–3450
Hawe A, Sutter M, Jiskoot W (2007) Extrinsic fluorescent dyes as tools for protein characterization. Pharm Res 25:1487–1499
He H, Mortellaro MA, Leiner MJP, Fraatz RJ, Tusa JK (2003) A fluorescent sensor with high selectivity and sensitivity for potassium in water. J Am Chem Soc 125:1468–1469
Heilemann M, van de Linde S, Mukherjee A, Sauer M (2009) Super-resolution imaging with small organic fluorophores. Angew Chem Int Ed 48:6903–6908
Herschel Sir JFW (1845) On a case of superficial colour presented by a homogeneous liquid internally colorless. Phil Trans Roy Soc London 135:143–145
Hirabayashi K, Hanaoka K, Shimonishi M, Terai T, Komatsu T, Ueno T, Nagano T (2011) Selective two-step labeling of proteins with an off/on fluorescent probe. Chem Eur J 17:14763–14771
Hirano T, Kikuchi K, Urano Y, Nagano T (2002) Improvement and biological applications of fluorescent probes for zinc, ZnAFs. J Am Chem Soc 124:6555–6562
Hirata T, Terai T, Komatsu T, Hanaoka K, Nagano T (2011) Development of a potassium ion-selective fluorescent sensor based on 3-styrylated BODIPY. Bioorg Med Chem Lett 21:6090–6093
Hof M, Hutterer R, Fidler V (eds) (2010) Fluorescence spectroscopy in biology: advanced methods and their applications to membranes, proteins, DNA, and cells. Springer, Berlin
Huang B, Bates M, Zhuang X (2009) Super-resolution fluorescence microscopy. Annu Rev Biochem 78:993–1016
Im C-N, Kang N-Y, Ha H-H, Bi X, Lee JJ, Park S-J, Lee SY, Vendrell M, Kim YK, Lee J-S, Li J, Y-H FB, Ng H-H, Yun S-W, Chang Y-T (2010) A fluorescent rosamine compound selectively stains pluripotent stem cells. Angew Chem Int Ed 49:7497–7500
Izumi S, Urano Y, Hanaoka K, Terai T, Nagano T (2009) A simple and effective strategy to increase the sensitivity of fluorescence probes in living cells. J Am Chem Soc 131:10189–10200
Jiang P, Guo Z (2004) Fluorescent detection of zinc in biological systems: recent development on the design of chemosensors and biosensors. Coord Chem Rev 248:205–229
Johnson I, Spence MTZ (eds) (2010) The molecular probes handbook, 11th edn. Life Technologies, Carlsbad
Juskowiak B (2011) Nucleic acid-based fluorescent probes and their analytical potential. Anal Bioanal Chem 399:3157–3176
Kamiya M, Asanuma D, Kuranaga E, Takeishi A, Sakabe M, Miura M, Nagano T, Urano Y (2011) β-Galactosidase fluorescence probe with improved cellular accumulation based on a spirocyclized rhodol scaffold. J Am Chem Soc 133:12960–12963
Kamiya M, Johnsson K (2010) Localizable and highly sensitive calcium indicator based on a BODIPY fluorophore. Anal Chem 82:6472–6479
Kapuscinski J (1995) DAPI: a DNA-specific fluorescent probe. Biotech Histochem 70:220–233
Kawazoe Y, Shimogawa H, Sato A, Uesugi M (2011) A mitochondrial surface-specific fluorescent probe activated by bioconversion. Angew Chem Int Ed 50:5478–5481
Ke S, Wen X, Gurfinkel M, Charnsangavej C, Wallace S, Sevick-Muraca EM, Li C (2003) Near-infrared optical imaging of epidermal growth factor receptor in breast cancer xenografts. Cancer Res 63:7870–7875
Kenmoku S, Urano Y, Kojima H, Nagano T (2007) Development of a highly specific rhodamine-based fluorescence probe for hypochlorous acid and its application to real-time imaging of phagocytosis. J Am Chem Soc 129:7313–7318
Keppler A, Gendreizig S, Gronemeyer T, Pick H, Vogel H, Johnsson K (2003) A general method for the covalent labeling of fusion proteins with small molecules in vivo. Nat Biotechnol 21:86–89
Kikuchi K, Komatsu K, Nagano T (2004) Zinc sensing for cellular application. Curr Opin Chem Biol 8:182–191
Kim HM, Cho BR (2009) Two-photon probes for intracellular free metal ions, acidic vesicles, and lipid rafts in live tissues. Acc Chem Res 42:863–872
Kim HM, Kim BR, Hong JH, Park J-S, Lee KJ, Cho BR (2007) A two-photon fluorescent probe for calcium waves in living tissue. Angew Chem Int Ed 46:7445–7448
Kim E, Koh M, Ryu J, Park SB (2008) Combinatorial discovery of full-color-tunable emissive fluorescent probes using a single core skeleton, 1,2-dihydropyrrolo[3,4-β]indolizin-3-one. J Am Chem Soc 130:12206–12207
Kim PKM, Zamora R, Petrosko P, Billiar TR (2001) The regulatory role of nitric oxide in apoptosis. Int Immunopharmacol 1:1421–1441
Kiyose K, Kojima H, Nagano T (2008) Functional near-infrared fluorescent probes. Chem Asian J 3:506–515
Koide Y, Urano Y, Hanaoka K, Piao W, Kusakabe M, Saito N, Terai T, Okabe T, Nagano T (2012) Development of NIR fluorescent dyes based on Si-rhodamine for in vivo imaging. J Am Chem Soc 134:5029–5031
Koide Y, Urano Y, Hanaoka K, Terai T, Nagano T (2011) Evolution of group 14 rhodamines as platforms for near-infrared fluorescence probes utilizing photoinduced electron transfer. ACS Chem Biol 6:600–608
Koide Y, Urano Y, Kenmoku S, Kojima H, Nagano T (2007) Design and synthesis of fluorescent probes for selective detection of highly reactive oxygen species in mitochondria of living cells. J Am Chem Soc 129:10324–10325
Kooy NW, Royall JA, Ischiropoulos H, Beckman JS (1994) Peroxynitrite-mediated oxidation of dihydrorhodamine 123. Free Radic Biol Med 16:149–156
Krishna TR, Parent M, Werts MHV, Moreaux L, Gmouh S, Charpak S, Caminade A-M, Majoral J-P, Blanchard-Desce M (2006) Water-soluble dendrimeric two-photon tracers for in vivo imaging. Angew Chem Int Ed 45:4645–4648
Lakowicz JR (2006) Principles of fluorescence spectroscopy, 3rd edn. Springer, New York
Lamy CM, Sallin O, Loussert C, Chatton J-Y (2012) Sodium sensing in neurons with a dendrimer-based nanoprobe. ACS Nano 6:1176–1187
Latt SA, Stetten G (1976) Spectral studies on 33258 Hoechst and related bisbenzimidazole dyes useful for fluorescent detection of deoxyribonucleic acid synthesis. J Histochem Cytochem 24:24–33
Lazarides T, McCormick TM, Wilson KC, Lee S, McCamant DW, Eisenberg R (2011) Sensitizing the sensitizer: the synthesis and photophysical study of Bodipy-Pt(II)(diimine)(dithiolate) conjugates. J Am Chem Soc 133:350–364
Le Guennic B, Maurya O, Jacquemin D (2012) Aza-boron-dipyrromethene dyes: TD-DFT benchmarks, spectral analysis and design of original near-IR structures. Phys Chem Chem Phys 14:157–164
Lee J-S, Kim HK, Feng S, Vendrell M, Chang Y-T (2011) Accelerating fluorescent sensor discovery: unbiased screening of a diversity-oriented BODIPY library. Chem Commun 47:2339–2341
Lee HD, Lord SJ, Iwanaga S, Zhan K, Xie H, Williams JC, Wang H, Bowman GR, Goley ED, Shapiro L, Twieg RJ, Rao J, Moerner WE (2010) Superresolution imaging of targeted proteins in fixed and living cells using photoactivatable organic fluorophores. J Am Chem Soc 132:15099–15101
Li F, Yang H, Hu H (2010) Luminescent rare earth complexes as chemosensors and bioimaging probes. In: Huang C (ed) Rare earth coordination chemistry: fundamentals and applications. Wiley (Asia), Singapore, pp 529–570
Lim MH, Wong BA, Pitcock WH Jr, Mokshagundam D, Baik M-H, Lippard SJ (2006) Direct nitric oxide detection in aqueous solution by copper(II) fluorescein complexes. J Am Chem Soc 128:14364–14373
Lippert AR, van de Bittner GC, Chang CJ (2011) Boronate oxidation as a bioorthogonal reaction approach for studying the chemistry of hydrogen peroxide in living systems. Acc Chem Res 44:793–804
Lo LC, Chu CY (2003) Development of highly selective and sensitive probes for hydrogen peroxide. Chem Commun (21):2728–2729
Los GV, Encell LP, McDougall MG, Hartzell DD, Karassina N, Zimprich C, Wood MG, Learish R, Ohana RF, Urh M, Simpson D, Mendez J, Zimmerman K, Otto P, Vidugiris G, Zhu J, Darzins A, Klaubert DH, Bulleit RB, Wood KV (2008) HaloTag: a novel protein labeling technology for cell imaging and protein analysis. ACS Chem Biol 3:373–382
Losonczy A, Makara JK, Magee JC (2008) Compartmentalized dendritic plasticity and input feature storage in neurons. Nature 452:436–441
Loudet A, Burgess K (2007) BODIPY dyes and their derivatives: syntheses and spectroscopic properties. Chem Rev 107:4891–4932
Luo S, Zhang E, Su Y, Cheng T, Shi C (2011) A review of NIR dyes in cancer targeting and imaging. Biomaterials 32:7127–7138
Ma Q, Su X (2011) Recent advances and applications in QDs-based sensors. Analyst 136:4883–4893
Maçôas E, Marcelo G, Pinto S, Cañeque T, Cuadro AM, Vaquerob JJ, Martinhoa JMG (2011) A V-shaped cationic dye for nonlinear optical bioimaging. Chem Commun 47:7374–7376
Maeda H, Fukuyasu Y, Yoshida S, Fukuda M, Saeki K, Matsuno H, Yamauchi Y, Yoshida K, Hirata K, Miyamoto K (2004) Fluorescent probes for hydrogen peroxide based on a non-oxidative mechanism. Angew Chem Int Ed 43:2389–2391
Marcus RA (1993) Electron transfer reactions in chemistry: theory and experiment (Nobel lecture). Angew Chem Int Ed Engl 32:1111–1121
Marks KM, Rosinov M, Nolan GP (2004) In vivo targeting of organic calcium sensors via genetically selected peptides. Chem Biol 11:347–356
Martin BR, Giepmans BNG, Adams SR, Tsien RY (2005) Mammalian cell-based optimization of the biarsenical-binding tetracysteine motif for improved fluorescence and affinity. Nat Biotechnol 23:1308–1314
Matsui A, Umezawa K, Shindo Y, Fujii T, Citterio D, Oka K, Suzuki K (2011) A near-infrared fluorescent calcium probe: a new tool for intracellular multicolour Ca2+ imaging. Chem Commun 47:10407–10409
Meier SD, Kovalchuk Y, Rose CR (2006) Properties of the new fluorescent Na+ indicator CoroNa Green: comparison with SBFI and confocal Na+ imaging. J Neurosci Methods 155:251–259
Miller EW, Lin JY, Frady EP, Steinbach PA, Kristan WB Jr, Tsien RY (2012) Optically monitoring voltage in neurons by photoinduced electron transfer through molecular wires. Proc Natl Acad Sci USA 109:2114–2119
Minta A, Kao JPY, Tsien RY (1989) Fluorescent indicators for cytosolic calcium based on rhodamine and fluorescein chromophores. J Biol Chem 264:8181–8178
Minta A, Tsien RY (1989) Fluorescent indicators for cytosolic sodium. J Biol Chem 264:19449–19457
Miyawaki A (2011) Development of probes for cellular functions using fluorescent proteins and fluorescence resonance energy transfer. Annu Rev Biochem 80:357–373
Mizukami S, Watanabe S, Hori Y, Kikuchi K (2009) Covalent protein labeling based on noncatalytic β-lactamase and a designed FRET substrate. J Am Chem Soc 131:5016–5017
Muyskens M (2006) The fluorescence of Lignum nephriticum: a flash back to the past and a simple demonstration of natural substance fluorescence. J Chem Educ 83:765–768
Myochin T, Kiyose K, Hanaoka K, Kojima H, Terai T, Nagano T (2011) Rational design of ratiometric near-infrared fluorescent pH probes with various pK a values, based on aminocyanine. J Am Chem Soc 133:3401–3409
Nagano T (2009) Bioimaging probes for reactive oxygen species and reactive nitrogen species. J Clin Biochem Nutr 45:111–124
Namkung W, Padmawar P, Mills AD, Verkman AS (2008) Cell-based fluorescence screen for K+ channels and transporters using an extracellular triazacryptand-based K+ sensor. J Am Chem Soc 130:7794–7795
Niu Y, Peng Q, Deng C, Gao X, Shuai Z (2010) Theory of excited state decays and optical spectra: application to polyatomic molecules. J Phys Chem A 114:7817–7831
Nolan EM, Lippard SJ (2009) Small-molecule fluorescent sensors for investigating zinc metalloneurochemistry. Acc Chem Res 42:193–203
Ogawa M, Kosaka N, Choyke PL, Kobayashi H (2009) In vivo molecular imaging of cancer with a quenching near-infrared fluorescent probe using conjugates of monoclonal antibodies and indocyanine green. Cancer Res 69:1268–1272
Ojida A, Honda K, Shinmi D, Kiyonaka S, Mori Y, Hamachi I (2006) Oligo-Asp tag/Zn(II) complex probe as a new pair for labeling and fluorescence imaging of proteins. J Am Chem Soc 128:10452–10459
Padmawar P, Yao X, Bloch O, Manley GT, Verkman AS (2005) K+ waves in brain cortex visualized using a long wavelength K+- sensing fluorescent indicator. Nat Methods 2:825–827
Razgulin A, Ma N, Rao J (2011) Strategies for in vivo imaging of enzyme activity: an overview and recent advances. Chem Soc Rev 40:4186–4216
Rehm D, Weller A (1970) Kinetics of fluorescence quenching by electron and H-atom transfer. Israel J Chem 8:259–271
Reinert KC, Dunbar RL, Gao W, Chen G, Ebner TJ (2004) Flavoprotein autofluorescence imaging of neuronal activation in the cerebellar cortex in vivo. J Neurophysiol 92:199–211
Robinson D, Besley NA, O’Shea P, Hirst JD (2011) Di-8-ANEPPS emission spectra in phospholipid/cholesterol membranes: a theoretical study. J Phys Chem B 115:4160–4167
Rosania GR, Lee JW, Ding L, Yoon H-S, Chang Y-T (2003) Combinatorial approach to organelle-targeted fluorescent library based on the styryl scaffold. J Am Chem Soc 125:1130–1131
Rust MJ, Bates M, Zhuang X (2006) Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM). Nat Methods 3:793–795
Sakabe M, Asanuma D, Kamiya M, Iwatate RJ, Hanaoka K, Terai T, Nagano T, Urano Y (2013) Rational design of highly sensitive fluorescence probes for protease and glycosidase based on precisely controlled spirocyclization. J Am Chem Soc 135:409–414
Samanta A, Vendrell M, Dasa R, Chang Y-T (2010) Development of photostable near-infrared cyanine dyes. Chem Commun 46:7406–7408
Shen Z, Lu Z, Chhatbar PY, O’Herron P, Kara P (2012) An artery-specific fluorescent dye for studying neurovascular coupling. Nat Methods 9:273–276
Shepherd J, Hilderbrand SA, Waterman P, Heinecke JW, Weissleder R, Libby P (2007) A fluorescent probe for the detection of myeloperoxidase activity in atherosclerosis-associated macrophages. Chem Biol 14:1221–1231
Shieh CC, Coghlan M, Sullivan JP, Gopalakrishman M (2000) Potassium channels: molecular defects, diseases, and therapeutic opportunities. Pharmacol Rev 52:557–593
Shimomura O, Johnson FH, Saiga Y (1962) Extraction, purification and properties of aequorin, a bioluminescent protein from the luminous hydromedusan, Aequorea. J Cell Comp Physiol 59:223–239
Shults MD, Janes KA, Lauffenburger DA, Imperiali B (2005) A multiplexed homogeneous fluorescence-based assay for protein kinase activity in cell lysates. Nat Methods 2:277–284
Skala MC, Riching KM, Gendron-Fitzpatrick A, Eickhoff J, Eliceiri KW, White JG, Ramanujam M (2007) In vivo multiphoton microscopy of NADH and FAD redox states, fluorescence lifetimes, and cellular morphology in precancerous epithelia. Proc Natl Acad Sci USA 104:10494–10499
Somers RC, Bawendi MG, Nocera DG (2007) CdSe nanocrystal based chem-/bio- sensors. Chem Soc Rev 36:579–591
Srikun D, Albers AE, Nam CI, Iavarone AT, Chang CJ (2010) Organelle-targetable fluorescent probes for imaging hydrogen peroxide in living cells via SNAP-tag protein labeling. J Am Chem Soc 132:4455–4465
Stokes GG (1845) On the change of refrangibility of light. Phil Trans Roy Soc London 142:463–562
Takahashi A, Camacho P, Lechleiter JD, Herman B (1999) Measurement of intracellular calcium. Physiol Rev 79:1089–1125
Terai T, Kikuchi K, Urano Y, Kojima H, Nagano T (2012) A long-lived luminescent probe to sensitively detect arylamine N-acetyltransferase (NAT) activity of cells. Chem Commun 48:2234–2236
Terai T, Nagano T (2008) Fluorescent probes for bioimaging applications. Curr Opin Chem Biol 12:515–521
Tomat E, Nolan EM, Jaworski J, Lippard SJ (2008) Organelle-specific zinc detection using zinpyr-labeled fusion proteins in live cells. J Am Chem Soc 130:15776–15777
Tour O, Adams SR, Kerr RA, Meijer RM, Sejnowski TJ, Tsien RW, Tsien RY (2007) Calcium Green FlAsH as a genetically targeted small-molecule calcium indicator. Nat Chem Biol 3:423–431
Toutchkine A, Kraynov V, Hahn K (2003) Solvent-sensitive dyes to report protein conformational changes in living cells. J Am Chem Soc 125:4132–4145
Trapani V, Farruggia G, Marraccini C, Iotti S, Cittadinia A, Wolf FI (2010) Intracellular magnesium detection: imaging a brighter future. Analyst 135:1855–1866
Tsien RY (1980) New calcium indicators and buffers with high selectivity against magnesium and protons: design, synthesis, and properties of prototype structures. Biochem 19:2396–2404
Tsien RY (1998) The green fluorescent protein. Annu Rev Biochem 67:509–544
Ueno T, Urano Y, Setsukinai K, Takakusa H, Kojima H, Kikuchi K, Ohkubo K, Fukuzumi S, Nagano T (2004) Rational principles for modulating fluorescence properties of fluorescein. J Am Chem Soc 126:14079–14085
Umezawa K, Nakamura Y, Makino H, Citterio D, Suzuki K (2008) Bright, color-tunable fluorescent dyes in the visible-near-infrared region. J Am Chem Soc 130:1550–1551
Urano Y, Asanuma D, Hama Y, Koyama Y, Barrett T, Kamiya M, Nagano T, Watanabe T, Hasegawa A, Choyke PL, Kobayashi H (2009) Selective molecular imaging of viable cancer cells with pH-activatable fluorescence probes. Nat Med 15:104–109
Urano Y, Kamiya M, Kanda K, Ueno T, Hirose K, Nagano T (2005) Evolution of fluorescein as a platform for finely tunable fluorescence probes. J Am Chem Soc 127:4888–4894
Veal EA, Day AM, Morgan BA (2007) Hydrogen peroxide sensing and signaling. Mol Cell 26:1–14
Vendrell M, Zhai D, Er JC, Chang Y-T (2012) Combinatorial strategies in fluorescent probe development. Chem Rev 112:4391–4420
von Prowazek S (1914) Über Fluorescenz der Zellen. Kleinwelt 6:37–40
Waggoner AS (1979) Dye indicators of membrane potential. Ann Rev Biophys Bioeng 8:47–68
Wahler D, Badalassi F, Crotti P, Reymond J-L (2002) Enzyme fingerprints of activity, and stereo- and enantioselectivity from fluorogenic and chromogenic substrate arrays. Chem Eur J 8:3211–3228
Walkup GK, Imperiali B (1997) Fluorescent chemosensors for divalent zinc based on zinc finger domains. Enhanced oxidative stability, metal binding affinity, and structural and functional characterization. J Am Chem Soc 119:3443–3450
Wardman P (2007) Fluorescent and luminescent probes for measurement of oxidative and nitrosative species in cells and tissues: progress, pitfalls, and prospects. Free Radic Biol Med 43:995–1022
Weissleder R, Ntziachristos V (2003) Shedding light onto live molecular targets. Nat Med 9:123–128
Whitaker JE, Haugland RP, Prendergast FG (1991) Spectral and photophysical studies of benzo[c]xanthene dyes: dual emission pH sensors. Anal Biochem 194:330–344
Whitney MA, Crisp JL, Nguyen LT, Friedman B, Gross LA, Steinbach P, Tsien RY, Nguyen QT (2011) Fluorescent peptides highlight peripheral nerves during surgery in mice. Nat Biotechnol 29:352–356
Wysockia LM, Lavis LD (2011) Advances in the chemistry of small molecule fluorescent probes. Curr Opin Chem Biol 15:752–759
Yap YW, Whiteman M, Cheung NS (2007) Chlorinative stress: an under appreciated mediator of neurodegeneration? Cell Signal 19:219–228
Yu FH, Catterall WA (2003) Overview of the voltage-gated sodium channel family. Genome Biol 4:207.1–207.7
Yuan L, Lin W, Yang Y, Chen H (2012) A unique class of near-infrared functional fluorescent dyes with carboxylic-acid-modulated fluorescence ON/OFF switching: rational design, synthesis, optical properties, theoretical calculations, and applications for fluorescence imaging in living animals. J Am Chem Soc 134:1200–1211
Zhai D, Lee S-C, Vendrell M, Leong LP, Chang Y-T (2012) Synthesis of a novel BODIPY library and its application in the discovery of a fructose sensor. ACS Comb Sci 14:81–84
Zhang J, Campbell RE, Ting AY, Tsien RY (2002) Creating new fluorescent probes for cell biology. Nat Rev Mol Cell Biol 3:906–918
Zlokarnik G, Negulescu PA, Knapp TE, Mere L, Burres N, Feng L, Whitney M, Roemer K, Tsien RY (1998) Quantitation of transcription and clonal selection of single living cells with β-lactamase as reporter. Science 279:84–88
Acknowledgments
We thank Dr. Toru Komatsu for the helpful comments on the manuscript. We are also grateful for the financial support from the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant no. 22000006 to T.N. and T.T. and grant no. 23651231 to T.T.). T.T. was also supported by the Cosmetology Research Foundation and Mochida Memorial Foundation for Medical and Pharmaceutical Research, Japan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Terai, T., Nagano, T. Small-molecule fluorophores and fluorescent probes for bioimaging. Pflugers Arch - Eur J Physiol 465, 347–359 (2013). https://doi.org/10.1007/s00424-013-1234-z
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-013-1234-z