放射性药物摄取的生理机制

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 localizationIsotope dilutionCapillary blockadePhysicochemical adsorptionCellular migration and sequest

2、rationMembrane transportSimple diffusionDiffusion and intracellular metabolism/bindingDiffusion and mitochondrial bindingDiffusion and increased capillary and plasma membrane permeabilityFacilitated diffusionActive transportPhagocytosisReceptor-mediated endocytosisMetabolic Substrates and Precursors

3、Precursors: Radiolabeled Amino Acids Tissue HypoxiaCell ProliferationSpecific Receptor BindingRadiolabeled PeptidesSteroid Hormone ReceptorsAdrenergic Presynaptic Receptors and StorageLDL ReceptorsRadiolabeled AntibodiesImaging Gene ExpressionIn vivo, MUGA, RBC scanMAA lung perfusionMDP bone scanWBC

4、 scan, denatured RBC spleen scanXe-133 ventilationHMPAO/ECD brain perfusion scanTc-99m MIBIDiffusion and increased capillary & plasma membrane permeabilityGallium 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

6、(of normal & tumor tissue)gallate:鎵酸鹽Gallium citrateLeaving 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 dif

7、fusion of unbounded 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 augmen

8、t the transport of the 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. AffinityThe dissociation constant has molar units (M)The smaller the dissociation constant, the more tightly bou

9、nd the ligand is, or the higher the affinity between ligand and protein.KdKd越小，解離度越小越小，解離度越小 ( (親和力越高親和力越高) )Facilitated diffusionF-18 FDG: facilitated diffusionGlucose: Glucose transporter protein family (GLUT1-6)Hepatobiliary agentsIDA derivativesTc99m disofenin & Tc-99m mebrofeninBlood v. to

10、hepatocyte membrane: -diffuse through pores in endothelium 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: passiveTc-99m

11、disofeninTc-99m mebrofeninActive transportAgainst concentration 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 functionRadioiodide and Tc-99m pert

12、echnetate anionsThyroidActively traps certain anions: I-, TcO4- 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

13、poolSalivary glands, stomach, bowel & GU tractAlso significant uptake (secretion) of radioiodide and pertechnetateThallous chloride (Tl-201) & Rubidium-82Tl(OH)2+ & Rb + act as K + ionUptake of myocardium involves (Tl & Rb):Passive diffusionATP-dependent pathwaysUptake by tumor cells

14、 (Tl-201)Increased blood flow and increased permeabilityNa+/K+ ATPaseCellular uptake (Tl-201)Na+/K+ ATPase oubain, digitalis and furosemideChloride cotransport system furosemidCalcium-dependent ion channel: minimal amountblockblockAddictive blockade effectRenal agentsAgents for GFRI-125 iothalamate,

15、 Tc-99m DTPA, Cr-51 EDTAMostly filtered by glomerulusNo specific transport mechanism involvedDependents on hydrostatic & colloid osmotic pressureAgents for ERPFOIH and MAG3Partly filtered and mostly secreted by tubulesActively transported by renal hippurate anionic transport systemPhagocytosisTc

16、-99m sulfur colloid (SC) Size: 0.1-1.0 umOpsonins (specific serum proteins) may interact with it, providing a coating 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

17、it from circulationIn SC scan, cold lesion in liver suggests tumor displacing the usual distribution of RES cellsSimilarly, radiation damage in liver & bone is seen as cold areas due to decrease RES functionHepatic lobule, sinusoid and Kupffer cellsFrom WikiPedia, Kupffer cellCentrilobular Kupff

18、er 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(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 interstiti

19、al space into lymphatic vessels and significant retentionNormal LNs hot spotsCancerous nodes cold (not sequest SC), FP resultLymphoscintigraphy: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

20、-99m SC: 0.1-1.0 umNot available in the U.S.Receptor-mediated endocytosisGa-67 and Fe-59 uptake by tumor involves the transferrin receptorsPro.:In vitro: low concentration of transferrin ( FDG-6-PFDG-6-P fructose-6-PFDG-6-P FDGhexokinaseGlucose-6-phosphate isomeraseGlucose-6-phosphatase此反應無法進行，因為G6P

21、 isomerase的structural & geometric demand很嚴格此反應所需enzyme很少或幾乎沒有Metabolic Substrates and Precursors radiolabeled amino acidsAmino 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-t

22、yrosineL-3- 18 F-a-methyltyrosine (FMT): relatively easy to synthesize, high in vivo stability (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 & glioblastoma7. Tissue Hyp

23、oxiaMISO (misonidazole)A radiosensitizer used in radiation therapy to cause normally resistant hypoxic tumor cells to become sensitive to the treatmentWith radiosensitizing and antineoplastic properties. Exhibiting high electron affinity, misonidazole induces the formation of free radicals and deple

24、tes radioprotective thiols, thereby sensitizing hypoxic cells to the cytotoxic effects of ionizing radiation. This single-strand breaks in DNA induced by this agent result in the inhibition of DNA synthesis.NCI Drug DictionaryWikipediaMISO造影/uptake原理retention of FMISO2007 European Radiology Vol. 17 Issue 4, p 861-72可離開細胞可離開細胞Tracers i