Tel. 061-379-7271 / Fax. 061-379-7280 / E-mail. jjmin@chonnam.ac.kr (molecular biology), (cell biology) (non-invasive in vivo imaging) / (1-4). (fluorescence), (bioluminescence), SPECT, PET, MRI,, / ( 1). (translational research). [ 18 F]-FDG ([ 18 F]2-deoxy-2-fluoro-D-glucose) PET. (molecular photonic imaging) (photon) (PET), (optical imaging). 1. multimodal molecular imaging. PET, CT, MRI, micropet, microct, animal MRI, high frequency US bioluminescence system, fluorescence sytem. (1) PET ( ) / 21
PET (specific marker).,, natural biological molecule,, molecular probe, reporter probe, marker, tracer. PET, molecule. probe PET, ( 2). [ 18 F]2-deoxy- 2-fluoro-D-glucose (FDG) fluorine-18 ( 18 F). PET 18 F FDG, probe (intravascular compartment) (extravascular compartment) (intracellular compartment). FDG, (glucose transporter) hexokinase II. FDG hexokinase II, hexokinase II. FDG 18 F. (annihilation event), 511 kev 180. (scintillation crystal) (photomultiplier tube) PET. (annihilation event) (coincident event). PET (50,000~100,000). FDG, filtered-back projection (attenuation correction).,,, FDG. PET 18 F 11 C, 15 O, 13 N, 14 O, 64 Cu, 62 Cu, 124 I, 82 Rb, 68 Ga, 76 Br. (cyclotron), ( 18 F 110 ).. PET micropet. PET 6 3 ~8 3 mm 3, PET ~3 3 mm 3. micropet ~2 3 mm 3, ~1 3 mm 3 micropet. PET 10-11 ~10-12 M/L. MRI 10-4 ~10-5 M/L., (optical image). PET 10 6 10 9. PET 2. PET 22
,, (5). (2) In Vivo (In Vivo Optical Imaging) in vitro ex vivo, luminometer. in vivo imaging. bioluminescence (targeted bioluminescence probe), (nearinfrared fluorochrome), (activatable near-infrared fluorochrome), (red-shifted fluorescence protein)...,. (charged coupled device, CCD). silicon-based detector. 400-1000nm, 2-3 ev CCD. CCD. CCD CCD chip thermal noise. Thermal noise CCD chip 20 C 10, CCD -120~-150 C (cooled CCD)., CCD. CCD (1). CCD.,.,,., cooled CCD 2. rotating CCD, single CCD volumetric image. CCD PM tube (6). 1) In Vivo Bioluminescence in vivo bioluminescence (, bacteria,,, ) (luciferase). luciferase,,,, 3. Bioluminescence /. Firefly luciferase (fluc) Luciferase D-luciferin. fluc D-luciferin. fluc. 23
, ATP.. luciferase.,, - ( 3). luciferase mammalian tissue. 600nm,., 600~1100nm. luciferase Photinus Pyralis firefly luciferase (Fluc), 560nm 600nm in vivo. Fluc D-luciferin oxyluciferin.,, ATP (7). bioluminescence -. (1) Fluc (external light excitation), D-luciferin, ATP,,. (2) D-luciferin turnover (T 1/2 =3h). (3). Fluc. 2) In Vivo Fluorescence Fluorescence (395~600nm), CCD. (, green fluorescence protein; GFP) in vivo. GFP 395nm 509nm. GFP EGFP (enhanced GFP) GFP 35. Coral discosoma red fluorescence protein (RFP) 558nm 583nm. Bioluminescence fluorescence autofluorescence. in vivo (1, 7). (Near-infrared fluorescent dye) Fluorescence protein, fluorescent dye in vivo. 700~900nm.,, (600~1000nm). Weissleder dye. Cathepsin B & H, matrix metalloprotease-2 (MMP-2) (8, 9). Fluorophores GFP RFP Cy5.5 ICG (indocyanine green) (excitation wavelength) 395-490nm 500-550nm 620-670nm 710-785nm (emission wavelength) 500-575nm 575-650nm 695-770nm 810-885nm 24
(1) (reporter gene). chloramphenicol acetyl transferase (CAT), alkaline phosphatase, α-galactosidase (lac Z).,,,,. green fluorescent protein (GFP) luciferase.,. PET,,. (reporter probe) (reporter gene) (10, 11). (2) /. 1). 2). 3). 4). 5). (.) 6). 7). 8). 9). ( 7 Kb.) 10). 11) mrna/. 12),. /.,. /. (3) PET 1) Cytosine deaminase Cytosine deaminase (CD) cytosine uracil. CD cytosine uracil. CD 5-25
fluorocytosine 5-fluorouracil CD 5-fluorocytosine. CD 6-[ 3 H]-5-fluorocytosine CD (human glioblastoma) 6-[ 3 H]-5-fluorouracil. 6-[ 3 H]-5-fluorocytosine. CD (10).. HSV1-TK, thymidine ( ; 5-iodo- 2-fluoro-2-deoxy-1-â-D-arabinofuranosyl-5-iodouracil (FIAU)) acyclogunosine ( ; 9-(4-[ 18 F]-fluoro-3-hydroxymethylbutyl)-guanine ([ 18 F]FHBG)) ( 4). HSV1-TK. Thymidine FIAU [ 131 I] [ 124 I], HSV1-TK 2) Herpes-simplex virus type-1 thymidine kinase thymidine kinase. ATP deoxythymidine deoxythymidine monophosphate (dtmp). (herpes simplex virus) thymidine kinase (herpes simplex virus thymidine kinase, HSV-TK) ( HSV1-TK, HSV1-tk.). thymidine kinase thymidine kinase deoxythymidine,. (12). Acyclovir (9-(2-hydroxyethoxymethyl)guanine) HSV- TK. HSV-TK acyclovir monophosphate guanylate kinase acyclovir diphosphate, acyclovir triphosphate. Acyclovir triphosphate DNA DNA DNA polymerase DNA. HSV1-TK gancyclovir (9-[[2-hydroxy-1-(hydroxymethyl)ethoxy] methyl]guanine) pencyclovir (9-(4-hydroxy-3-hydroxymethylbutyl)guanine). HSV1- tk, 4. HSV-tk TdR (thymidine), 5-methyluracil-2 -deoxyribose; FIAU, 2 -fluoro-2 -deoxy-b-d-arabinofuranosyl-5-iodouracil; FIRU, 2 -fluoro-2 -deoxy-5-iodo-1-b-d-ribofuranosyl-uracil; FMAU, 2 -fluoro-2 -deoxy-5-methyl-1-b-d-arabinofuranosyluracil; FEAU, 2 -fluoro-2 -deoxyarabinofuranosyl-5-ethyluracil; IVFRU, 2 -fluoro-2 -deoxy-5-iodovinyl-1-b-ribofuranosyl-uracil; IUdR, 2 -deoxy-5-iodo-1-b-d-ribofuranosyl-uracil; ACV, 9-[(2-hydroxy-1-ethoxy)methyl]guanine (acyclovir); GCV, 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl]guanine (ganciclovir); PCV, 9-[4-hydroxy-3-(hydroxymethyl)butyl]guanine (penciclovir); FGCV, 8-fluoro-9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)methyl] guanine (fluoroganciclovir); FPCV, 8-fluoro-9-[4-hydroxy-3-(hydroxymethyl)butyl]guanine (fluoropenciclovir); FHPG, 9-[(3-fluoro-1-hydroxy-2-propoxy)methyl]guanine; FHBG, 9-(4-fluoro-3-hydroxymethylbutyl)guanine. 26
. HSV1-tk [ 124 I]FIAU. FIAU acycloguanosine derivatives HSV1-TK, TK (13, 14). Acycloguanosine acyclovir (ACV) ganciclovir (GCV), penciclovir (PCV) HSV1-TK, PCV [ 18 F] [ 18 F]FHBG (15, 16). HSV1-tk HSV1-sr39tk acycloguanosine HSV1-tk FIAU (17). 3) -2-2 (dopamine-2 receptor, D 2 R) striatum. D2R D 2 R 3-(2-[ 18 F]-fluoroethyl)spiperone ([18F]FESP) PET, [ 123 I]iodobenzamine SPECT (18). PET / D 2 R [ 18 F]FESP D 2 R mrna.. (19). D 2 R G (G gycoprotein coupled receptor, GPCR) (secondary messenger) protein kinase.. 4) Human type 2 somatostatin receptor (hsstr2) hsstr2. [ 111 In]Octreotide, [ 99m Tc]P829, and [ 99m Tc]P2045, hsstr2 [ 99m Tc]P2045 (20). 5) Sodium/iodide symporter sodium/iodide symporter (NIS). ([ 123 I], [ 131 I]) [ 99m Tc]pertechnetate.., NIS (21). (4) (Optical Imaging) 1) Firefly luciferase luciferase Photinus Pyralis firefly luciferase (Fluc), 560nm 600nm in vivo. Fluc D-luciferin oxyluciferin.,, ATP. Fluc -, in vivo luciferin 20.,,, 1. ATP (22). 2) Renilla luciferase renillar reniformis Fluc luciferase renilla luciferase (Rluc) 27
. coelenterazine enthalpy. Fluc,, ATP, ATP. Fluc - in vivo. coelenterazine. 480 nm, 600 nm (23, 24). 3) Gaussia luciferase Gausia princeps renilla luciferase luciferase (25). Gaussia luciferase (Gluc). Gluc Rluc coelenterazine. (quantum yield) Rluc 200 Fluc, Rluc 480 nm. 4) Bacterial luciferase Vibrio harveyi, Vibrio fischeri, Photorhabdus luminescens lux A, B, C, D, E (operon) lux A, lux B bacterial luciferase lux C, lux D, lux E fatty acid reductase enzyme complex. reduced flavin mononucleotide (FMNH 2 ) 490 nm. luciferase, bacterial operon (26). 5) Green fluorescence protein Green fluorescence protein (GFP) Aequorea victoria. cofactor (excitation wavelength),. 450-490 nm 510-570 nm.?,, GFP. GFP (27). 6) Red fluorescence protein R. Tsien discosoma DsRed DNA. 500-550 nm 575-650 nm. 600nm. DsRed tetramer monomeric red flurescence protein (28). (1). 1) PET SPECT, 2) MRI, 3) PET ( 5) (29). 1) (I-124, Cu- 64, In-111, I-123, Tc-99m ), SPECT, PET.,,., 28
, 48 75%.,,. 2) MRI MRI. MRI,.,,, 2., MRI, (30). 3) PET,.,.,,,., (31). (2) Bacterial luciferase in vivo (In Vivo 5.. ( ) In-111.,. ( ) MRI.. ( ) firefly luciferase PET HSV1-tk, PET.. Imaging of Light-Emitting Bacteria) In vivo bioluminescence. bacterial luciferase (Lux) soil bacterium Photorhabdus luminescens lux operon. lux operon 5, lux A, B luciferase, lux C, D, E 3. firefly luciferase. lux 500nm. (light-emitting bacteria),. lux operon. 29
1) IRES (IRES based approach) internal ribosomal entry sites (IRES)... IRES. 6.. lux, 6. GFP. H&E (A) Gram (B), DAPI, Texas red F-actin (C-H) 1 (C, D), 5 (E, F), 7 (G, H). (C, E, G; 600 D, F, H; 1200 ), ( 6) (26, 32). 2) (Fusion gene approach) (fusion gene).,. 3) (Dual-promoter approach). IRES,,. (3) (Imaging Gene Therapy). ( 7).. (33). 4) (Co-administration approach).,.. 5) (Bidirectional transcriptional approach) Tetracycline-responsive element (TRE) minimal 30
7. 5 CMV. TRE rtetr-vp16 transactivator, rtetr-vp16 tetracycline doxycycline TRE. IRES,., (imaging of bi-directional inducible gene expression). (4) (Imaging Transcriptional Regulation) constitutive promoter CMV... Green. (endogenous gene) 8. 2 (Two-step transcriptional amplification system, TSTA).. GAL-4/VP-16 GAL-4 2. 1 GAL-4/VP-16. GAL-4/VP-16 2 GAL-4 VP-16. (, CEA, PSA, p53) (34). /. (transcription activation domain) VP16 DNA GAL4, GAL4 2 (Two step transcriptional amplification system, TSTA system) ( 8). TSTA 12~15 (35-37)., PSA (key regulating element) (multimerization) 31
(34). (5).,.,. (adoptive immunotherapy),., (38)., PET SPECT,,...,. PET 6. PET [ 64 Cu]pyruvaldehydebis(N4-methylthiosemicarbazone) ([ 64 Cu]PTSM) (39).,...,. HSV1-tk, NIS, Fluc, (38). (6) (Molecular Interaction Imaging), GAL4-VP16 TSTA.,. Ray NF-kB (VP16-MyoD GAL4-ID) (40). Paulmurugan (41-43). (7) (Near-infrared fluorescent dye) cathepsin B & H, matrix metalloprotease-2 (MMP-2). µm (quenched)., (unquenched). indocyanine green (ICG) cy5.5 fluorescent dye,. smart probe, (, ) (44-46). PET,,.,,. 32
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