A to Z of Drug Design

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A to Z of Drug Design
Pharmaceutical
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Development of drugs in Nuclear Medicine

• Drug development from concept to application

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People Involved inRadiopharmaceutical Development

• Everyone has specific technical expertise.
• Radiopharmaceutical development is a combination
  of work.

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• Product Design
• Preparation
• Organic synthesis
• Ligands
• Inorganic synthesis
• Optimized yields gt90
• Complex stability
• Nuclear Chemistry
• Isotope production
• Radiolabelling experiments

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• In Vitro studies
• Cell studies
• Uptake
• Localization
• Receptor binding assays
• Affinity
• Computer modeling
• Structure determination
• Synthesis
• Peptides, antibodies

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• In Vivo studies
• Animal studies
• Uptake
• Normal biodistribution
• Interpretation of Biological Function
• Where does it go? Why?
• Target studies
• Receptor binding
• Cancer, tumor models

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• Clinical Studies involving Humans
• Phase I, II, and III
• Determine effectiveness
• Positive and Negative effects
• Patient Administration
• Optimize dose
• Future Studies and further evaluation

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Part 2 Practical Applications of Radionuclides
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Preparing a Radiopharmaceutical

• Simple preparation
• One step preparation of a kit
• Addition of nuclide and heating
• High yield (gt99)
• Cost
• Companies weigh benefit vs. expense

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Kit Formulations

• Ingredients
• Ligand
• Preservatives (Citrate, Cyclodextran, )
• Reducing agent (Tin, Borohydride)
• Additions
• Radioactive material
• Preparation
• Stir
• Heat
• Analyze (Quality Control)
• Paper Chromatography

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So you want to inject your radiopharmaceuticals,
is it

• Quality Control
• Sterile
• No living things (i.e., spores, bacteria)
• Pyrogen free
• Fever causing agents
• Isotonic (ionic strength)
• Physiological pH (7.4)
• Calibrated for patient

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Current Radiopharmaceuticals

• Discuss major radionuclides utilized in Hospitals
• Look at organ specific radiopharmaceuticals

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Its a Tc world after all.

• gt90 of radiopharmaceuticals for imaging contain
  99mTc
• PET isotope production and usage has improved in
  recent years.
• HMO approval F-18 use and increase in of PET
  centers
• Limitations

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Technetium Background

• Tc discovered in 1937 by Perrier and Segré, who
  separated it from a Mo deflector plate after
  years of deuteron irradiation in the Berkeley
  cyclotron
• 17 known isotopes of Tc - all radioactive
• 99mTc (T1/2 6.03 h) is most widely used in
  Nuclear Medicine - discovered in 1938 by Seaborg
  and Segré
• 99Tc (T1/2 2.1 x 105 y) is produced by U
  fission used to establish chemistry of the
  element under conventional chemical
  concentrations
• 92Tc, 93Tc and 94mTc have shorter T1/2s (4-165
  min), and have potential use as PET radionuclides

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Background, contd

• Comments on patent application of Green, Richards
  and Tucker in 1958 for 99Mo/99mTc generator
• While this method is probably novel, it appears
  the product will probably be used mostly for
  experimental purposes in the laboratory. On this
  basis no further patent action is believed
  warranted Atomic Energy Commission
• We are not aware of a potential market for
  99mTc We would recommend against filing
  Research Corporation for Associated Universities,
  Inc.
• First injection of 99mTcO4- into a human was made
  in 1961, following development of the BNL
  generator
• By 1970, it was estimated that more than 2000
  daily diagnostic procedures were carried out in
  the U.S.
• By 1985 market for 99mTc was gt30 million

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Types of External Imaging

• Planar Imaging
• 2D pictures
• Dynamic Imaging
• 4D (3D as a function of time)
• Single photon Emission Computed Tomography
  (SPECT)
• Positron Emission Tomography (PET)

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Heart Imaging Agents
SPECT Imager

• Mimic the cationic charge of potassium uptake
• 201Tl heart agent
• 167 KeV (9) EC
• Behavior similar to K
• Tc-99m agents
• Complex formation

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99mTcSestimibi (Cardiolite)

• Tc 1 oxidation state
• Six monodentate isonitrile ligands
• Ligand exchange with copper (I) tertakis analog
• Myocardial Ischemia and Infarcts
• Localizes in the mitochondria

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Sestimibi for Breast Cancer
Dual purpose agent!
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Tc-Tetrofosmin (Myoview) TcQ-12
(Techneheart)

• Tc 5 oxidation state
• Dioxo core (180)
• Two bidentate phosphine chelates
• Reversible myocardial Ischemia and Infarcts

• Tc 3 oxidation state
• Trans phosphine (180)
• Tetradentate Schiff base compound
• Myocardial Ischemia and Infarcts

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Lung Ventilation Agents

• Ventilation
• Indicates the presence of any obstruction in the
  airways
• Xe-133
• Radioactive gas, no chelate, no biomolecule, just
  inhale
• Kr-81m (T1/213 sec)
• Limited utility due to short half life
• Tc-99m Aerosol
• Nebulized Tc DTPA

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99mTc Macroalbumin Aggregated (MAA) Perfusion
Agent
Particle size 10-100 nmParticle number
100,000-200,000Dose 5 mCi Non-specific
labeling methodPhysiologyEnd arteriole
occlusion Normal biodistribution lung
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Liver Agents

• Biological blood filter.
• Hydrophobic neutral complexes absorbed in the
  liver.
• Heavy organic molecules
• Sulfur containing
• Compounds degraded (phagocytosis) to more useful
  pieces or oxidized and excreted as waste.
• Identifies liver function and morphology
• cirrhosis

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99mTc-Sulfur Colloid

• Formation
• Reduced Tc with Elemental sulfur
• Accumulation
• Liver, spleen, and bone marrow.
• Sulfurs indication clearance pathway
• Similar biological half life as Tc
• Non specific labeling

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99mTc Iminodiacetic acid derivatives (IDA)

• Longer alkyl chain (X,Y, Z) attenuate liver
  uptake
• Phenyl ring (Lipophillic)
• Tridentate coordination
• N, two COO
• Octahedral
• Tc(ligand)2

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Infection and Liver
67Ga Citrate Energy 93 (40), 184 (20), 300
(17), 393 (20) KeV T1/2 78 hrs Iron
analogue Normal biodistribution liver, spleen,
bone, bone marrow,Uses Infection, tumorUptake
by dissociation (pH) Binds to Lactoferrin
(Luekocytes)Natural exchange rxn
Tc-MDP
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Bone Imaging

• 99mTc-MDP
• TcO(MDP)2
• Dose 25 mCi
• Methylene Diphosphonate
• Adsorbed onto hydroxappatite (bone matrix)
• 40-50 of compound will go to the bone after 3-4
  hrs
• Normal biodistribution
• bone, kidney, bladder
• Uses infection, trauma, tumor
• Renal clearance

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Bone Therapy

• 153Sm-EDTMP (Quadramet)
• Energy 103 keV g (5 )
• T1/2 46 hrs
• Dose 1 mCi/kg
• Physiology
• EDTMP like MDP
• Normal biodistribution bone, bladder, kidney
• Uses treatment of painful bone metastases
• Can image weak g

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Brain Imaging

• Diffusion or target specific mode to cross the
  blood brain barrier
• Must be a lipophilic and neutral compound
• TcECD, TcHMPAO, F-18(FDG)
• Nondiffusible
• TcO4- and TcDTPA

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Tc Ethyl Cysteinate Dimer (Neurolite)

• 5 oxidation state
• Mono oxo
• Square pyramidal ECD diffuses into brain, then
  metabolized.
• Only the l, l analog is metabolized
• Converts to a polar species

Hypoperfusion
Normal
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TcHMPNAO (Ceratec)

• Brain imaging
• Neutral lipophillic
• 5 oxidation state
• Only d,l conformation shows uptake

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Parkinsons Disease
Used to Investigate Dopamine transport levels
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Kidney Uptake

• Primary mode of excretion of fluids from the
  body.
• Total blood volume passes every 3-5 min
• Two modes of uptake in the Kidneys
• Glomerular filtration and tubular secretion.

• Two RP utilized
• I-131 and Tc-99m
• Maximum uptake in 4-5 minutes
• Charged hydrophillic complexes excreted

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Iodine The original radionuclide of
Radiopharmaceuticals

• I-123 EC (100), T1/2 13.2 hr, g 159 KeV (83)
• I-125 EC (100), T1/2 60 d, g 35 KeV (7)
• I-131b- (100), T1/2 8 d, g 284 (6), 364
  (81), 637(7)

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123I vs. 131I
Which on is which?
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Kidney Agents
Tc-DPTA

• Hippuran
• I-131
• b- emitter
• and g emitter
• Poorer imaging

• Tc-99m
• Tc(5), anionic (-1) complex
• Tubular secretion

• Tc-99m
• Tc(4), -1 complex
• Golmerular filtration Rate (GFR) secretion

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Kidney Uptake Comparison
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Thyroid

• Treatment of hyperthyroidism
• I-131 b- particle
• Incorperated into metalbolic pathway of
  triiodothyronine (T3) or thyroxine (T4)
  synthesis.
• Thyroid cancers can be treated the same

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PET Imaging

• The positron (b) annihilation with thermal
  electron
• (180) two 511 KeV gammas
• Coincidence counting
• Simultaneous detection

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18Fluorodeoxglucose (FDG)

• b emission
• PET scans
• Sugar metabolic pathway
• Non specific
• Rate dependence on cell type
• Brain, heart, tumor,
• dementia, alzheimers,
• Drug abuse
• ADHD

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Conclusions

• Radioactive materials provide an active method to
  study biological processes
• Kinetic or rate information
• Non evasive
• Tunable for target or organ specific
• Wide applicability to biological systems