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1、Pathophysiology and mechanisms of radiopharmaceutical localization_cont.,20140721 morning meeting 胡蓮欣,The Pathophysiological basis of Nuclear Medicine 2nd ed.Springer.,The mechanisms of radioisotope localization,Isotope dilutionCapillary blockadePhysicochemical adsorptionCellular migration and seque
2、strationMembrane transportSimple diffusionDiffusion and intracellular metabolism/bindingDiffusion and mitochondrial bindingDiffusion and increased capillary and plasma membrane permeabilityFacilitated diffusionActive transportPhagocytosisReceptor-mediated endocytosisMetabolic Substrates and Precurso
3、rsPrecursors:Radiolabeled Amino Acids Tissue HypoxiaCell ProliferationSpecific Receptor BindingRadiolabeled PeptidesSteroid Hormone ReceptorsAdrenergic Presynaptic Receptors and StorageLDL ReceptorsRadiolabeled AntibodiesImaging Gene Expression,In vivo,MUGA,RBC scan,MAA lung perfusion,MDP bone scan,
4、WBC scan,denatured RBC spleen scan,Xe-133 ventilation,HMPAO/ECD brain perfusion scan,Tc-99m MIBI,Diffusion and increased capillary&plasma membrane permeability,Gallium citrate:a carrier-free Ga-67Still no general agreement on the exact mechanisms of localization in tumorsBound exclusively to transfe
5、rrin:two specific metal-binding sites of the iron-transport glycoprotein Ga-transferrin complex slowly transported through the capillary v.wallor exist as(under physiological pH 7.4)Ga(OH)4-:a soluble gallate ion rapidly leaves the blood compartment and equilibrates with the interstitial fluid(of no
6、rmal&tumor tissue),gallate:鎵酸鹽,Gallium citrate,Leaving blood vesselBounded form leaves BV slowly,by transportFree form leaves BV rapidly and equilibrates with interstitial fluidUptake by normal cells/tumor cellsNormal cells:strongly promoted by binding to transferinTumor cells:simple diffusion of un
7、bounded or loosely bound form of Ga-67Retention in cellsTumor cell:very much dependent on Ga-67 binding to iron-binding proteins(lactoferin&ferritin,high affinity)prevent back diffusion of free Ga-67 Increased capillary permeability and expanded extracellular space would augment the transport of the
8、 macromolecules(transferrin)across the BVIncreased permeabiltiy of tumor cell membrane,(沒有unbounded form可以進去的路),(有unbounded form可以進去的路),Dissociation constant(Kd)vs.Affinity,The dissociation constant has molar units(M)The smaller the dissociation constant,the more tightly bound the ligand is,or the h
9、igher the affinity between ligand and protein.,Kd越小，解離度越小(親和力越高),Facilitated diffusion,F-18 FDG:facilitated diffusionGlucose:Glucose transporter protein family(GLUT1-6)Hepatobiliary agentsIDA derivativesTc99m disofenin&Tc-99m mebrofeninBlood v.to hepatocyte membrane:-diffuse through pores in endothe
10、lium lining-binding to the anionic membrane bound carriersHepatocyte membrane to intracellular:-facilitated by carrier-mediated,non-sodium-dependent,organic anionic pathways(similar to bilirubin)Intracellular to biliary tract:passive,Tc-99m disofenin,Tc-99m mebrofenin,Active transport,Against concen
11、tration gradientRequires energyATP(primary active transporters)Electrochemical gradient of Na+or H+(secondary active transporters)If the energy source is inhibited or removed,the transport system will not function,Radioiodide and Tc-99m pertechnetate anions,ThyroidActively traps certain anions:I-,Tc
12、O4-and ClO4-(same pathway)Competitive to each otherOnly iodine is used to synthesize thyroid hormone;others diffuse out of the glandAffected by iodine containing medications,TSH levels,thyroid&nonthyroid drugs,total body iodine poolSalivary glands,stomach,bowel&GU tractAlso significant uptake(secret
13、ion)of radioiodide and pertechnetate,Thallous chloride(Tl-201)&Rubidium-82,Tl(OH)2+&Rb+act as K+ionUptake of myocardium involves(Tl&Rb):Passive diffusionATP-dependent pathwaysUptake by tumor cells(Tl-201)Increased blood flow and increased permeabilityNa+/K+ATPaseCellular uptake(Tl-201)Na+/K+ATPase o
14、ubain,digitalis and furosemideChloride cotransport system furosemidCalcium-dependent ion channel:minimal amount,block,block,Addictive blockade effect,Renal agents,Agents for GFRI-125 iothalamate,Tc-99m DTPA,Cr-51 EDTAMostly filtered by glomerulusNo specific transport mechanism involvedDependents on
15、hydrostatic&colloid osmotic pressureAgents for ERPFOIH and MAG3Partly filtered and mostly secreted by tubulesActively transported by renal hippurate anionic transport system,Phagocytosis,Tc-99m sulfur colloid(SC)Size:0.1-1.0 umOpsonins(specific serum proteins)may interact with it,providing a coating
16、 to the SC particlesBe recongnized by receptors on the phagocytic cell surfaces(of RES,called Kupffer cells in liver sinusoids;reticular cells in spleen)Engulf the colloid,remove it from circulationIn SC scan,cold lesion in liver suggests tumor displacing the usual distribution of RES cellsSimilarly
17、,radiation damage in liver&bone is seen as cold areas due to decrease RES function,Hepatic lobule,sinusoid and Kupffer cells,From WikiPedia,Kupffer cell,Centrilobular Kupffer cells,with a grey granular cytoplasm,in a resolving liver injury.Liver biopsy.Trichrome stain.,溶液的分類,以溶劑分類:水溶液非水溶液以型態分類:氣態溶液(
18、一般稱混合氣體)/液態溶液(簡稱溶液)/固態溶液(亦稱固溶體)以溶液導電性分類:電解質溶液非電解質溶液以溶質粒子大小分類,0.001-0.1 um,教育部數位教學資訊入口網,Phagocytosis,Sentinel LN mapping:Particles 0.1 um:rapid clearance from the interstitial space into lymphatic vessels and significant retentionNormal LNs hot spotsCancerous nodes cold(not sequest SC),FP resultLymph
19、oscintigraphy:Ideal agents for their small size:Tc-99m antimony:0.002-0.015 umTc-99m human serum albumin:0.001-0.002 umA replacement that needs filter(0.2 um filter)Tc-99m SC:0.1-1.0 um,Not available in the U.S.,Receptor-mediated endocytosis,Ga-67 and Fe-59 uptake by tumor involves the transferrin r
20、eceptorsPro.:In vitro:low concentration of transferrin(0.1 mg/ml)stimulated and increased tumor uptake of Ga-67Transferrin receptors in tumor cells are 10X than in normal cellsAgainst:In vivo:conflicting data from animal studiesGa-67 tumor uptake also was observed in mice with congenitally absent tr
21、ansferrin(hypotransferrinemic)The exact connection bt transferrin receptors&Ga-67 tumor uptake in vivo has not been establishedAlso see Diffusion and increased capillary&plasma membrane perme.,6.Metabolic Substrates and Precursors metabolic trapping of FDG,FDG:F-18-2-deoxy-2-fluoro-d-glucoseDevelope
22、d in 1977,by Some et al.Transported into cell by facilitated diffusion(see also Facilitated diffusion)FDG FDG-6-PFDG-6-P fructose-6-PFDG-6-P FDG,hexokinase,Glucose-6-phosphate isomerase,Glucose-6-phosphatase,此反應無法進行，因為G6P isomerase的structural&geometric demand很嚴格,此反應所需enzyme很少或幾乎沒有,Metabolic Substrat
23、es and Precursors radiolabeled amino acids,Amino acid transportL-methyl-11 Cmethionine(MET)L-O-2-18 Ffluorethyl-tyrosine(FET)Protein synthesisL-1-11 Ctyrosine(TYR)L-2-18 Ffluorotyrosine(FTyr)L-4-18 Ffluoro-m-tyrosineL-3-18 F-a-methyltyrosine(FMT):relatively easy to synthesize,high in vivo stability(
24、75%inj.dose appears unmetabolized form in the circulation)Unnatural amino acids(nonmetabolized)C-11 ACBC(11 Ca-aminocyclobutane carboxylic acid)F-18 ACBCIn astrocytoma&glioblastoma,7.Tissue Hypoxia,MISO(misonidazole)A radiosensitizer used in radiation therapy to cause normally resistant hypoxic tumo
25、r cells to become sensitive to the treatmentWith radiosensitizing and antineoplastic properties.Exhibiting high electron affinity,misonidazole induces the formation of free radicals and depletes radioprotective thiols,thereby sensitizing hypoxic cells to the cytotoxic effects of ionizing radiation.T
26、his single-strand breaks in DNA induced by this agent result in the inhibition of DNA synthesis.,NCI Drug Dictionary,Wikipedia,MISO,造影/uptake原理,retention of FMISO,2007 European Radiology Vol.17 Issue 4,p 861-72,可離開細胞,Tracers in tissue hypoxia,F-18 FMISO(F-18 fluoromisonidazole)Cu-64 ATSM(Cu-diacetyl
27、bis-(N4-methylthiosemicarbazone)I-123 IAZA(I-123 iodoazomycin arabinoside)Tc-99m PnAO(TcO(PnAO-1-(2-nitroimidazole)a Tc-99m propylene amine oxime derivative of 2-nitroimidazole)a.k.a.BMS181321Tc-99m HL91(4,9-diaza-3,3,10,10-tetramethyldodecan-2,11-dione dioxime),NO2 moiety related,NO2 moiety Non-rel
28、ated,SPECT,PET,PET,SPECT,SPECT,Cu-64 ATSM,I-123 IAZA,Tc-99m PnAO,F-18 FMISO,Tc-99m HL91,Hypoxia&tumor pH,Tumor cells have increased rates of anaerobic&aerobic glucose metabolism.1925,by WarburgIf aerobic respiration is not available,pyruvate(end product of glycolysis)turned into lactic acid by LDH(lactate dehydrogenase)and accumulates pH of tumor cell is lightly acidic,as compared with normal tissue pH of 7.4,
