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Generalities

Generalities. Physical form: Gas/aerosols Liquid solids. Partial pressure solubility. Saturation/non saturation. Soluble/unsoluble. Miscibility. Dimensions Hardness. Equilibration/diffusion Micelles (liposomes). Colloids Microspheres macroaggregates.

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Generalities

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  1. Generalities • Physical form: • Gas/aerosols • Liquid • solids Partial pressure solubility Saturation/non saturation Soluble/unsoluble Miscibility Dimensions Hardness Equilibration/diffusion Micelles (liposomes) Colloids Microspheres macroaggregates

  2. Radiopharmaceuticals compounds can be classified according to their physical form. • Their disposition throughout the body will then depend upon interaction with physiological processes mostly occurring from blood and fluid transportation: • Blood flow: • (µspheres & macroaggregates remain trapped into the capillary bed and their number is proportional to blood stream through capillaries themselves). • Blood is able to absorb and eliminate gases. Some gases (CO) form stable binding with the blood and remains into the blood (blood volume) • Nanocolloids are used to image lynphatic transport.

  3. Examples lynphoscintigraphy 99mTc-Re Sulphur colloids 99mTc-microspheres 99mTc-labelled macroaggregates 11CO labelled blood (inhalation) 133Xe gas (isot. Solut.) 81mKr (from Rb generator) Lung perfusion Blood volume Tissue perfusion Perfusion = blood flow/mass of tissue Blood volume = only intravascular tracers not diffusing into tissues Access to venous blood by intra venous administration or arterial blood via inhalation

  4. Overall molecular characteristics Simple molecules Medium sized (500-6000) macromolecules Molecular weight Polarity High polarity hydrophilic Apolarity lipophilic The ratio polarity/MW is often used to drive penetration to biological processes. Small polar molecules will be eliminated by the kidney (urine), while larger less polar molecules will be excreted by the gallbladder/liver (feces). These characteristics are at the basis of tracers for monitoring function of emuntory organs (e.g. kidney or hepatosplenic impairment) The Blood Brain Barrier allows only lipophilic molecule to cross.

  5. Molecular structure/I Interaction is driven by the nature and identitity of the molecule or its specific chemical character/I Simple molecules Elements: 15O2……… 18F-………. 123I-………. 201Tl+…….. inorganic salts:67Ga-citrate.. 64Cu-ATSM. 99mTc04-…… Oxidative metabolism Bone turn-over Thyroid activity Na/K-ATPase Regional biochemistry (pH) Regional red-ox activity Specific tropism

  6. Molecular structure/II Interaction is driven by the nature and identitity of the molecule or its specific chemical character/II Complexes and organic molecules Transition metals  Complexes (Prof. Mazzi lectures) Bioactive molecules: Biochemical probes: enzyme substrates receptor ligands neurotransmitters transporters hormones vitamins ion-channels membranes growth factors ….. Used also as Pathology indicators: ipoxia inflammation proliferation protein synthesis energy consumption gene expression

  7. CH2OH O HO HO OH OH CH2OH O HO HO OH 18F In vivo biochemistry D-Glucose Red bars indicate H D-2-[18F]fluoro-2-deoxyglucose

  8. Blood flow Intercellular space Intracellular space Vascular space Glucose metabolism Entry into the cell Glycolysis Glycolysis Intracell. Glucose Glucose-6P Fructose-6P  lactate Pyruvate  Tricarboxylic acid cycle  CO2 + H2O + 38ATP Aerobic conditions Glucose metabolism is stricltly related to the cellular demand of energy: What does it happen with FDG

  9. Glycolysis Intracell. Glucose Glucose-6P Fructose-6P  lactate Pyruvate  Tricarboxylic acid cycle  CO2 + H2O + 38ATP STOP FDG The first enzyme (glucokinase) converts FDG into FDG-6P but the presence of the fluorine atoms is recognised by the second enzyme (phosphoglucoisomerase): FDG-6P is NOT a suitable substrate. FDG-6P accumulates intracellularly at a rate correlating the cellular need of energy. FDG is “metabolically Trapped” inside the cell Application: Abnormal anaerobic metabolism (myocardial ischaemia) Increased glucose metabolic rate (tumors, inflammation) Brain regional activation

  10. Blood flow Extracellular space Intracellular space Vascular space Measurement of myocardial blood flow Ammonia is normally produced by metabolic processes: it is eliminated with the urines and partially “recycled”. Ammonia diffuses freely (IN/OUT) across vessels and cellular membranes. Intracellular ammonia is conveted into glutamine. This compound is then valuable for the cell and doesn’t diffuse back. Tracer: 13NH3 (injected i.v.) Rationale: the amount of ammonia entering the cell is proportional to the concentration in the extracellular space which, in turn, is proportional to blood flow!

  11. PET Tracers (just a few!) [11C]Thymidine DNA synthesis [11C]Methyonine protein synthesis [11C]Thyrosine protein transport [18F]phenylalanine protein transport [11C]PIB labelled drug [11C]Tamoxifen labelled drug [11C]Doxorubicine labelled drug [18F]5-FUracyl labelled drug [15C]CO blood volume [15C]H2O blood flow [15O]O2 oxygen extraction [13N]NH3 myocardial blood flow [18F]NaF bone turn-over [18F]FDG glucose consumption [11C]Acetate oxidative metabolism [11C]palmitate Fatty acid metabolism [18F]MISO regional hypoxia [18F]Estradiol hormone receptor ligand [18F]spiperone D2 receptors [18F]DOPA dopamine pool

  12. O O 11CH3 C CH3 C OH OH O CH3 11C OH Radiopharmaceuticalpreparation/I Isotopic labelling: e.g. 11C for 12C , 18F for 19F Make the synthesis of the molecule using labelled precursors or reagents The biological acceptance is NOT changed due to isotopic effect (as it happens with tritium vs hydrogen) Acetic acid enters oxidative metabolism 11CH3MgI + CO2 CH3MgI + 11CO2 11C s 12C mass (isotopic) effect is negligible. Tritium (3H) mass is very different from 1H as well as its binding strenght. This may have important effects (kinetic effect) when this bond is involved (e.g. cleavage) into a biochemical process Using different precursors/reagents the exact position of introduction of the label can be (sometime) selected. In general different position may have different biochemical fate.

  13. Radiopharmaceuticalpreparation/II Mimetic labelling When the isotopic labelling cannot be used the structure of the region of the molecule that is responsible for the biologic activity must remain unchanged and the label has to be introduced into other regions either directly into the chemical structure (example A) or remotely via conjugating agents (example B) . Part of the molecule fitting the pocket Specific pocket of binding Example A Example B

  14. Labelling approaches Mimetic labelling Isotopic labelling Molecule: spiroperidol (ligand of D2 dopaminergic receptors)

  15. CYCLOTRON FOR RADIONUCLIDES PRODUCTION They can be regarded as the source of two exotic reagents: 1H+ 2H+ “loaded” with the proper kinetic energy

  16. Nuclear reactions

  17. Thin metal windows Bombardment Target chamber 1) Target gas BEAM VALVE 2) Target gas + Radiochemical precursor Cyclotron vacuum tank Cooling jacket (WATER) Mounting flange Tipical volume of target chamber 50-200 cc for gases (depending on proton range and gas pressure. 1-3 cc for liquid

  18. CH2OAc O AcO AcO 18F- AcO H OTf CH2OH O HO HO HO 18F H 18O (p,n)18F H18F (aq)  K18F (anhydrous) K18F  (K+/K222) 18F- (K+/K222) 18F- + TAM  AcetylFDG AcetylFDG hydrolysis  FDG Radiochemistry K222 binds to K+ and enhance fluoride reactivity in organic solvents TAM = FDG precursor (tetraacetymannose 2-triflate) Automatic synthesis module

  19. Radiotracciante Radiofarmacia Produzione dei Radionuclidi Radiochimica Acquisizione Immagini

  20. Generic flow-chart Cyclotron operation Target bombardment 140’ In-line radionuclide purification Radiochemical synthesis 40’ Quality control (in process) Purification Formulation 25’ Quality control Biological/Pharmaceutical Dispensing OFF-LINE Final formulation requires the solution to be sterile, pyrogen free, isotonic, pH adjusted (usually 4.5-8.5)

  21. Radiopharmaceutical design • Selection of the target • Body distribution and Tissue density of the target process • Critical review of possible substrates/ligands • Competition of endogenous molecules • Information about structure/biological activity relationships • Production of labelled metabolites • Once a biological target has been selected the project of a radiopharmaceuticals must combine a number of parameters: • Radionuclide half-life vs. time scale of the study (dependent on biological time of evolution) • Possible chemical reactions vs availabile precursors/reagents • Time scale of the synthesis, • chemical/radiochemical yields, • technological difficulties • Radiation protection • Purification and specific radioactivity (to be considered vs possible interference, competition, toxicity, drug effect)

  22. BLOOD LIVER k1 Plasma Compartment FDG Tissue Compartment FDG k2 “Solution Equation” k4 k3 Ctis(t) = (k1/2-1) [(k3+k4-1) e-1t + (2-k3-k4)e-2t] Cpl(t) + VCpl(t) 2,1 = (k2+k3+k4) ± sqrt [(k2+k3+k4)2 – 4k2k4] / 2 Tissue Compartment FDG-6-P Parametri derivati: Kiml.min-1.ml-1tissue = (K1.k3 )/(k2+k3) Three-compartment model

  23. “PET Imaging” Sagittal Coronal Transaxial

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