Molecular Imaging PDF

Molecular imaging Biomarker Imaging principle Imaging scale Morphological and Functional imaging Label-free and Probe based imaging 1 Molecular imaging provides relevant information for Drug Discovery and Development Molecul...

Molecular imaging Biomarker Imaging principle Imaging scale Morphological and Functional imaging Label-free and Probe based imaging 1 Molecular imaging provides relevant information for Drug Discovery and Development Molecular imaging: intersection of molecular biology and medicine, includes imaging techniques combining structural information and molecular signatures, enables the visualization of physiological processes and cellular functions. Biomarker: a laboratory measurement that reflects the activity of a (disease) process, predicts drug efficacy but can be wrong, predictor of therapeutic response not necessarily therapeutic outcome, should yield information on a critical path in the development of a pathology that is modulated by the therapeutic intervention. Imaging principles: Probe → Matter interaction → Detection → Image production Imaging Scale: size (nm → m), time (ms → y) General Concepts in Molecular Imaging Morphological imaging: identification of the structure of a biological system Functional imaging: identification of a cellular signature and event in a living system Hybrid imaging: combination of morphological and functional imaging Label-free/Probe free imaging: Target unspecific, predominantly for morphological imaging Probe based imaging: Target specific, predominantly for functional imaging  Molecular Probe design (reporter probes, methods and reporter genes) 2 Direct (targeted) reporter probes: Label part: Radionuclide, Fluorescent molecule, Paramagnetic metal complex or Air bubble Pharmacophore: small molecule, peptides, antibody, oligonucleotide, macromolecule, etc. Activatable reporter probes: non-active substrate gets activated upon binding the target (FRET, BRET) Direct method: Labelled drug lead: Structurally identical or very similar, pharmacological and pharmacokinetic characteristics similar; shares same target (Example: [11C]-Erlotinib) Indirect/surrogate method(s): Surrogate probe: Structurally different but competes for same target (Example: Eliprodil → [11C]NB1) or Surrogate probe and surrogate target: Structurally unrelated, Binds different target, Target and surrogate target are indirectly e.g. metabolically interconnected (Example: [18F]FDG (Glut1) → Tyrosin kinase receptor (gets phosphorylated by ATP of glucose metabolism)) Reporter gene: foreign gene is introduced into cell genom, a stimulus is expressing the gene, detected by reporter probe or the proteins own signal. Critical probe features: don’t change structure parts if important for molecule function Optical imaging Ultrasound 3  Optical imaging Ultrasound Probe Photon (λ = 300-800nm) Radiofrequency wave (λ < 1.5mm) Matter interaction Absorption, penetration, scattering Reflection Modalities Fluor-, Biolumin-, Phosphorescence Ultrasonography Resolution 1-5 / 1mm 50-100μm Chemical Probe Near infrared fluorochromes (NIR) None or microbubbles Application Cellular and Pre-clinical imaging Vascular and interventional imaging, pregnancy, thoracentesis Advantages High sensitivity (10-9M), functional imaging, no High spatial resolution, inexpensive, 4D, no ionizing radiation ionizing radiation, fast, non-invasive Limitations Only pre-clinical, low penetration in tissue, high Low sensitivity (10-4M), limited penetration absorption in tissue, mostly 2D depth, predominantly morphological imaging, inability to image through air-pockets or bone, quality highly dependent on the skill of the person Function A fluorophore (from organism itself or An original wave is reflected by an object, administered) gets excited by light, relaxes to a reflected wave gets detected, the distance lower energy state a photon is released with a between the source and the object can be different wavelength, which will be detected. measured. FRET: coming close → Fluorescence after excitation BRET: conformational change to get close → fluorescence after excitation MRI 4  Magnetic resonance imaging Probe Radiofrequency waves (non-ionizing) Matter interaction Nuclear spin transition Function: Modalities Magnetic resonance imaging (MRI), A magnetic field (0.5-14 Tesla) is applied which spectroscopy (MRS), functional MRI (fMRI), organizes the electrons of the water molecules hyperpolarized in the body into an anti- and parallel orientation (±54.7° to field). After field is turned off the Resolution 50-100μm electrons relax over time and return to a Chemical Probe None (H2O in the body) or paramagnetic random distribution. This relaxation time is contrast agents (Gd-, Fe-complex) different for different tissues and the change in Application Neurology, oncology, cardiology; tumor, brain, magnetic moment is picked up by spine, musculoskeletal system radiofrequency (RF) coils. These signals are converted to a digital signal by fourier Advantages Excellent soft tissue contrast, high spatial transformation. resolution, non-invasive MRI active nuclei: H-1, P-31, C-13, F-19 Limitations Low sensitivity (10-4M), poor hard matter contrast, predominantly morphological imaging, expensive, long scan times, strong magnetic field (e.g. contraindicated for patients with pacemakers, etc.) Typical probes Water molecules form chelated spheres around Ga, Fe, Mn which shortens the relaxation time (different spheres have different relaxation time) X-ray, CT 5  X-ray imaging, computer tomography Probe X-ray photons Matter interaction Transmission, absorption, scatter Function: Modalities X-ray (2D), computer tomography (CT,3D), X-ray from X-ray source radiates through the phase-contrast X-ray/CT body and is absorbed differently by different materials, which can be seen on the x-ray image Resolution 10-50μm (black = good transmission; white = bad Chemical Probe None or contrast agents transmission). Application Trauma, oncology, cardiology etc.; bone trauma, X-ray: 2D; CT: 3D (images from different angles) infarction, tumors, calcification, cardiac, angiography, fibrosis, pulmonary embolism Advantages Highest spatial resolution, inexpensive, fast, high contrast resolution, non-invasive Limitations Ionizing radiation (dose), poor soft tissue contrast, low sensitivity (10-3M), morphological imaging, radiation exposure: chest X-ray = 0.02 mSv, chest CT = 5-7 mSv Typical probes Compounds containing heavier elements (I, Ba, Th), absorb x-ray and give better contrast PET, SPECT 6  PET: Positron emission tomography SPECT: Single photon emission computed Function: tomography The γ-ray strikes the scintillation crystal (different material for different γ-ray energy: high (511 keV) → BGO or LSO; medium (100-200 Probe γ-ray, positron → γ-ray keV) → NaI) which will de-excited by emission of Matter interaction Transmission, absorption (annihilation), photons and a photon multiplier tube than scattering measures the light intensity and converts it to Modalities Positron emission tomography (PET), Single an electrical impulse that gets detected. A photon emission computer tomography (SPECT), collimator is used for higher accuracy in scintigraphy (2D) detection by absorption of non-parallel γ-rays. Resolution 5-10mm (in clinical application) PET: generally short-lived radioisotopes (min-h), stationary detection ring, uses positron emitting Chemical Probe Radiotracers, radiopharmaceuticals radioisotopes (positron gets emitted, elastic (radiolabelled molecules) bumps with electrons, travels more distance Application Neurology, oncology, cardiology, drug when emitted with more energy (worse R), until development, animals etc.; various organ 1022 keV when it will annihilate with an function (liver, kidney, thyroid, heart, lung, etc) electron, where two γ-ray are released in opposite directions). !decay and annihilation are Advantages Highest sensitivity of medical imaging spatially separated! techniques (10-10-10-12M), microdosing, functional imaging SPECT: generally long-lived radioisotopes (h-d), scintillation camera rotates around body, Limitations Ionizing radiation (dose), very expensive, poor reconstruction from 2D images to 3D, uses γ-ray spatial resolution emitting radioisotopes Typical probes Probes are needed and essential, radiolabelled molecules (further lectures) Radiopharmacy, Radiopharmaceutical Radioactive Decay, Radioactivity Specific Activity Half-life, effective half-life 7 Radiopharmacy: Preparation, characterization, and QC of radioactive materials for human use; molecular imaging and radionuclide therapy Radiopharmaceutical (=radiotracer): medicinal product containing a chem./biol. part (biolT1/2) with a radionuclide/- isotope for diagnosis or therapy (physT1/2). No pharmacological effect because of minimal application amount. Limited time from production to application, but GMP and QC still mandatory. (production max. 3 T 1/2) Radioactive decay: the random process of unstable nuclei undergoing transformation to release excess energy in form of ionizing radiation. Radioactivity (A): is defined as nuclear disintegrations per second (= 1/s = Becquerel [Bq]) 𝑙𝑛(2) 0.693 𝜆∗𝑁𝐴 𝑁 = 𝑁0 ⅇ −𝜆𝑡 → 𝐴 = 𝐴0 ⅇ −𝜆𝑡 𝑇1⁄ = = 𝐴𝑠𝑝𝑒𝑐 = 2 𝜆 𝜆 𝑀𝑊 Specific activity (Aspec): radioactivity per unit mass of a radionuclide [Bq/g] Half-life (T1/2): time any quantity of radionuclide needs to be decrease to half of its original quantity Effective half-life (effT1/2): Reduced lifetime of radiopharmaceuticals in organs due to biological transport, elimination or decay. If difference biol. and phys. T1/2 large, then effT1/2 is slightly less than the smaller one. If they have the same value, effT eff 1/2 is half the value. T1/2 is always smaller than the others each..𝑝ℎ𝑦𝑠 𝑇1⁄ ∗.𝑏𝑖𝑜𝑙 𝑇1⁄ 𝑑∗(𝐿+𝑍) 𝑒𝑓𝑓 2 2. 𝑇1⁄ = (𝑅) = 2.𝑝ℎ𝑦𝑠 𝑇 1⁄ +.𝑏𝑖𝑜𝑙 𝑇 1⁄ 𝐿 2 2 Resolution (R):  Types of decay (Chart, range, shielding, Crossfire effect) 8  α 𝐴 𝑍𝑃 → 𝐴−4 𝐷 + 42𝛼 Large/heavy nuclei, α-particle = 42𝐻ⅇ 2+. 𝑍−2 β- 𝑛 → 𝑝+ + 𝛽 − + 𝜈̅ 𝐴 𝑍𝑃 → 𝐴 𝑍+1 𝐷 + −10ⅇ + 𝜈̅ n-rich nuclei, emits a high energy e-. β+ 𝑝+ → 𝑛 + 𝛽 + + 𝜈 𝐴 𝑍𝑃 → 𝐴 𝑍−1 𝐷 + +10𝛽 + 𝜈 p+-rich nuclei, energy > 1022keV, positron is antimatter → elastic bumps. with e-, travels until 1022 keV energy → annihilate with an e- → 2 γ-ray 180° directions EC 𝑝+ + ⅇ − → 𝑛 + 𝜈 −10ⅇ + 𝐴 𝑍𝑃 → 𝐴 𝑍−1 𝐷 + 𝜈 Electron Capture:p+-rich nuclei, energy < 1022keV (insufficient energy to. form positron), inner e- gets catched by a p+ in the nucleus → forms n and ν, often the nucleus remains in an excited energy state and emits γ-ray IT 𝐴 Isomeric Transition: After any radioactive decay the nucleus sometimes has 𝑍𝐷 still some residual energy, which can be released by γ-radiation IC Internal Conversion (Conversion Electrons): The existing residual energy of the nucleus is transferred from the nucleus to an inner e-, which then has sufficient energy to fly off at high speed (internal conversion (IC) instead of γ-radiation). These e- have low energies (few 10 keV) Auger Electron: Auger electrons are produced e.g. after an EC, when an outer shell electron receives sufficient kinetic energy (from X-rays) to fly away (internal photo effect). These electrons have low energies (few 10 keV) A: # n & p (Massenzahl); Z: # p; N: # n; e : electron; n: neutron; p+: proton; β-: negatron; β+: positron; ν: neutrino; ν̅: antineutrino - Karlsruhe Nuclide Chart: lists all known isotopes of the chemical elements including their decay properties Some radiation penetrates matter more than other: γ-radiation > 100 mm, electrons (< 2 MeV) 100 mm, α particles (< 5 MeV) 0.1 mm. This also correlates with the requirements for the shielding of these radiation types. While α-radiation can be shielded with tissue, paper and skin, for β-radiation aluminium foil or plastic is needed and for γ-radiation many cm of lead or tungsten is needed. Crossfire effect: Drugs only have an effect where they bind, but the radiation of radiopharmaceuticals reaches some distance around where it has bound and therefore also treats/radiates the surrounding cells (who could be without the binding target/receptor). Important emitters for therapy and diagnosis (all decay types) 9 Radionuclide T1/2 Ø particle energy [keV] Ø γ-energy [keV] Spatial resolution [mm] Decay mode Ac-225 9.9 d 5935 - Ra-223 11.4 d 5979 144 Bi-213 45 min 5869 323 Y-90 64 h 930 - Lu-177 6.7 d 140 208 I-131 8d 190 364 Sm-153 46 h 226 103 Re-188 17 h 795 155 C-11 20 min 386 2x511 1.1 N-13 8 min 492 2x511 O-15 2 min 735 2x511 1.5 F-18 110 min 250 2x511 0.7 Cu-64 12.7 h 278 0.7 Ga-68 1.1 h 830 2x511 2.4 Br-76 16.3 h 1180 3.2 I-124 4.17 d 820 2x511 2.3 Zr-89 3.27 d 396 1.1 Ga-67 3.3 d 93, 185 EC Tc-99m 6.02 h 140 IT I-123 13.3 h 159 EC In-111 2.8 d 171, 245 EC Tl-201 3d 135, 167 EC α β- β+ γ-ray hello Important to learn: decay mode of radionuclide  Production of radionuclides (Bateman, transient & secular equilibrium) 10 Artificial radionuclides are predominantly produced via bombardment (irradiation) with high energy particles such as n, p, d or α-particles nuclear reactors (neutron bombardment) reactions: (n,γ), (n,p), (n,f=fission) {I-131, Sm-153, Ho-166, Lu- 177, W-188} cyclotrons use charged particles (p or d): (p,n), (p,2n), (d,n), (p,α) {C-11, N-13, F-18, Cu-64/67, In-111, I- 123} On-site generators are used to bring the isotope to the patient without access to a (expensive) reactor or a cyclotron. {Ga-68, Tc-99m, Re-188} A radioactive mother nuclide (p) decays to a radioactive daughter (d) → used in radiopharmaceuticals. The Bateman equation describes the abundances and activities in a decay chain as a function of time, based on the decay rates and initial abundances. 𝜆𝑑 𝐴𝑑 = 𝐴 𝑝 ∗ 𝜆 ∗ (1 − ⅇ −𝑡∗(𝜆𝑑 −𝜆𝑝 ) ) secular: 𝐴𝑑 = 𝐴𝑝 ∗ (1 − ⅇ −𝑡∗𝜆𝑑 ) 𝑑 −𝜆𝑝 Transient equilibrium: λd>λp (t1/2d < t1/2p) factor 10-50 → After max. activity of d → parallel decay to p (Ad>Ap) e.g. 99Mo/99mTc: 66h/6h Secular equilibrium: λd>>λp (t1/2d < t1/2p) factor > 100 → Simplified Bateman equation e.g. 68Ge/68Ga: 287d/68min  Clinically used generators General scheme of a generator 11 Generator T1/2p T1/2d 44Ti/44Sc 60.4 y 3.9 h 68Ge/68Ga 287 d 68 min 62Zn/62Cu 9.1 h 9.7 min 81Rb/81mKr 4.7 h 13.3 s m ≙ metastable 82Sr/82Rb 25 d 1.3 min partially stable before it decays further 90Sr/90Y 28.6 y 64.1 h 99Mo/99mTc 66 h 6h 113Sn/113mIn 115 d 1.67 h 225Ac/213Bi 10 d 46 min parent = unstable: decays on its own, different charge → released from column  Decay scheme of Mo-99 Scheme of a 99Mo/99mTcGenerator Elution profile 12 elution profile: 22.8 h convenient hospital {98Mo(n,γ)99Mo} 87.5% decay to 99mTc → activity curve slightly below Bateman! Thick (some cm’s) column shield cause 12.5% 99 Tc with 777 keV γ-radiation Mo-99 decays, the complex changes from [99MoO4]2- to [99mTcO4]1- → charge changed and makes ion exchange possible ==> so only Na[99mTcO4] is eluted from column!  SUV Factor determining tracer kinetics Compartment models (allg.) Reverse and irreversible binding How to choose a model 13  𝐵𝑞 𝑖𝑛 𝑡𝑖𝑠𝑠𝑢𝑒 𝑜𝑟 𝑜𝑟𝑔𝑎𝑛𝑠 (𝑃𝐸𝑇 𝑑𝑎𝑡𝑎) 𝑐𝑚3 Standardized Uptake Value 𝑆𝑈𝑉 = 𝐵𝑞 (𝑖𝑛𝑗𝑒𝑐𝑡𝑒𝑑 𝑑𝑜𝑠𝑒) 𝑔 (𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡) SUV = 1: homogenous distribution; inhomogenous: SUV > 1: more in region of interest (ROI), SUV < 1: less in ROI Factors determining tracer kinetics Characteristics of the ROI ∙ Blood flow (mL/min) irreversible: ∙ Tracer exchange between blood (plasma) and tissue ∙ Tracer metabolism in ROI ∙ Tracer interaction with the target (ir-/reversible binding, transport, metabolism) The compartment models kx: [1/min] (rate constant) One-tissue compartment, irreversible → 3 Ca, tracer conc. (Bq/cm ) in arterial plasma (input function) C1, tracer conc. (Bq/cm3) in tissue-compartment 1 One-tissue compartment, reversible Two-tissue compartment, reversible → C2, tracer conc. (Bq/cm3) in tissue-compartment 2 How to choose the model? Based on mechanism of uptake [18F]Flumazenil in mouse ∙ Reversible, irreversible (trapping) brain after i.v. bolus ∙ Radiometabolite in ROI ∙ Neuroreceptor tracers: often 2-tissue compartment model Different models must be compared to get the best fit  Compartment model curves Reference tissue model Specific and non-specific binding 14 1-tissue compartment model 2-tissue compartment model Reference tissue model Use a reference tissue (gives new input function) instead of the input function, often used for neuroreceptor tracers. The model rate constants together with the input function define the TAC of the region-of-interest (ROI) Non-/specific binding →  Types of radiation Ionizing radiation LET Gy and Sv, wR and wT 15  Type of Radiation Mass Charge Typical energy Range (in air/H2O) LET in H2O(keV/μm) wR α 4.0026 +2 4 -10 MeV 3-10 cm / 5-11 μm 20 -190 20 Protons 1.0078 +1 1 -200 MeV 2.3-250 cm / 2.3 μm-28 cm 8 -45 1 β- 0.000549 −1 0.3 -4 MeV 80-4200 cm / 0.09-2.5 cm 0.19 -0.3 1 β+ 0.000549 +1 0.3 -4 MeV 80-4200 cm / 0.09-2.5 cm 0.19 -0.3 1 Auger& Conversion Electrons 0.000549 −1 0-50keV 2-500 nm 4–26 keV Neutrons 1.0086 0 1 -15 MeV 43-101 mm / 68-160 mm 7 -175 5-20 X-ray 0 5-100 keV m/ mm 0.3 -3.0 1 γ 0 10 keV -10 MeV m / mm 0.2 1 Ionizing Radiation: Radiation possesses enough kinetic energy to liberate an electron from an atom or molecule = ionized matter In vivo leads to radiolysis of water (water to excite water to hydroxyl radial to peroxide) → direct interaction with DNA → Breaking of chemical bonds (ss- or ds breaks, base mutations) Linear Energy Transfer (LET): measure of energy transfer for ionizing radiation when traveling through matter LΔ=dEΔ(mean energy loss of the particle)/dx(traveling distance of the particle) High LET radiation means much energy gets free over little path therefore causing extensive damage. 1 Gray leads to: 4000-5000 DNA-damage/cell: 3000 nucleobase damages, 1000 single strand breaks, ca. 40 double strand breaks Sievert was design to represent stochastic biological effects of ionizing radiation. 1 Sv= 5.5% probability of developing cancer (ICRP103) wR is in reference to 60Co: γ= 58.6 keV and reverse proportional to LET (different radiation → different LET) = cellular response The organs different radiation sensitivity.  Dosimetry (absorbed, equivalent and effective dose) 16 Radiation, dose-effects and limitations 17 ICRP recommended max. additional dose rates Internal Radiation Dosimetry 18 For the majority of diagnostic radiopharmaceuticals most organs are source and targets ∑𝛥𝑖 𝜙𝑖 (𝑟𝑘 ←𝑟ℎ ) ̅ = 𝐴̃ ∗ 𝑆 = 𝐴0 ∗ 𝜏 ∗ 𝑆 = 𝐴ℎ ∗ 1.443 ∗.𝑒𝑓𝑓 𝑇1 ∗ 𝑆 𝐷 𝑆(𝑟𝑘 ←𝑟ℎ) = ⁄ 2 𝑚𝑘 Radiolabelling concepts 19 Covalent bonds: direct labelling of radiocarbon or radiohalogens, ‘organic’ radionuclides Coordinative bonds: labelling via metal chelators of peptides or proteins, radiometal labelling Selected bifunctional chelating agents (BFCA): molecule with a metal chelating unit and a functional group for binding to a biomolecule e.g. DOTATATE, PSMA, Zevalin Quality Control of Radiopharmaceuticals 20  Radionuclide purity = isotopic purity: which fraction of the total radioactivity is coming from the desired radionuclide. E.g. 99Mo detected with radioactivity through thick lead in 99mTc preparation, determination of the half-life or γ- spectrometry Radiochemical purity: which fraction of the total radioactivity is from the desired chemical form (no 99mTcO4-, hydrolysed 99mTc), determined trough HPLC, TLC; test & calc. see ↓ Sterility testing: Free of microorganisms like virus, bacteria, fungi and algae; Membrane Filtration: Product is filtered and the filter incubated, Are colonies forming?; Direct inoculation: Product is added to a bottle of growth medium and incubated, turbidity (Trübung) or precipitation? Endotoxin testing: LAL Test: Factor C from LAL reacts with endotoxins from gram-neg. bacteria to an activated protease, which releases the dye p-nitroaniline (yellow) from a synthetic peptide. Purity Criterial 99m Tc- pertech- netate  General Composition of a Kit 99m Tc-sestamibi kit with chemical reaction Mechanisms of accumulation of Tc-99m Radiotracer 21  Reduction of [99mTcO4]- Possible Mechanisms of Accumulation of a Tc-99m Radiotracer ∙ Passive transport/Diffusion ∙ Ion transport ∙ Antigen-antibody binding ∙ Adsorption/Chemisorption ∙ Sequestering of cells ∙ Metabolic trapping  99mTc-Chemistry Selected Tc-99m Radiopharmaceuticals 22 99mTc (and 186/188Re): A Special Case Large diversity of complexes Known oxidation states from -1 to +7 Most stable oxidation state +VII, +IV Most important oxidation states +7, +5, +3 and +1 Complex geometry depends on the oxidation state of the isotope; metal chelator systems 99m Tc Production: 99Mo/99mTc Generator, T1/2: 6 h, γ-energy: 140 keV, ideal SPECT, Decay mode: IT Selected examples of Tc-99m Radiopharmaceuticals 99m Tc-HMPAO, 99mTc-pertechnetate, 99mTc-Sestamibi, 99mTc-Tetrofosmin, 99mTc-MAG3, 99mTc-ECD, 99mTc- MDP, 99mTc-MAA, 99mTc-HIDA2 [99mTc]Tc(MAA): structure and oxidation state unknown [99mTc]Tc+III(HIDA)2: 99mTc-Etifenin, used for liver scintigraphy, lipophilic groups (R) facilitate the uptake/excretion via the liver ⃝ [99mTc]Pertechnetate [99mTc]HMPAO [99mTc]ECD 23 Na[99mTc]Tc+VIIO4 [99mTc]Tc+VO-d,l-HMPAO: 99m Tc-Exametazime, Ceretec® Oxidative state: +7 Thyroid imaging Oxidative state: +5 Penetration into the brain if BBB is damaged Neutral complexes (lipophilic); Penetrates the BBB Hot (autonomic adenoma) or cold nodule (Carcinoma, passively and is trapped by formation of a hydrophilic cyst, inflammation) complex mediated by glutathione, which is trapped in cell. CNS perfusion tracer [99mTc]Tc+V-O-L,L-ECD: Application: cold nodule due to a stroke 99m Tc-Bicisate Oxidative state: +5 Neutral complexes (lipophilic); Penetrates the BBB passively and is trapped by formation of a hydrophilic complex (esterases) Neurolite™ (Bristol-Myers Squibb) CNS perfusion tracer Hydrolysis of -COOEt to -COOH for trapping in cell [99mTc]Tetrofosmin [99mTc]Sestamibi 24 [99mTc]Tc+V(tetrofosmin)+: [99mTc+I(MIBI)6]+: 99mTc-Sestamibi 99m Oxidative state: +1 Tc-tetrofosmin Oxidative state: +5 Used for myocard scintigraphy Used for myocardial scintigraphy ∙ Octahedral complex ∙ Passive diffusion in cells ∙ Trapping of the cationic complexes in the cells of the myocardium. [99mTc]MAG3 [99mTc]MDP 25 [99mTc]Tc+V(MAG3)--: 99mTc-Mertiatide Oxidative state: +5 Used for measuring kidney function Anionic complex which is readily excreted via the kidneys [99mTc]Tc+V(Diphosphonates): 99mTc-MDP = 99mTc-Medronate Oxidative state: +5 MDP: Methylenebisphosphonicacid, medronicacid Adsorption of 99mTc-phosphonates complexes on Ca10(PO4)6(OH)2 (hydroxyapatite in bones) CAD 26 Coronary Artery Disease (also coronary/atherosclerotic heart Imaging Modalities for Evaluation of CAD disease) One of the leading causes of morbidity and mortality worldwide; requires a medical diagnosis No symptoms → chest pain (angina), heart failure → heart attack Reduced lumen diameter → Reduced blood flow Metabolism tracer [18F]FDG to evaluation Myocardial viability → Reduced myocardium (are heart cell still alive). perfusion SPECT and PET radiopharmaceuticals to identify the infarcted Stress: physical exercise or emotional (angry, excited) (irreversible) versus ischemic (reversible, only under stress Major Goals of Nuclear Cardiology Imaging reduced perfusion) myocardium. ∙ Earlier detection of the disease → From treatment to Nuclear Imaging: Myocardial Perfusion prevention ∙ When coronary arterial lumen diameter is reduced by 70% ∙ Better prognosis of the disease (risk assessment) → Chest pain occur during myocardial stress. ∙ Monitoring of therapies ∙ Reduced by 45% or 50% → Perfusion abnormality can be detected under stress conditions, but no symptoms. ∙ Myocardial perfusion imaging during stress and rest has been the most common clinical application of nuclear cardiology. Myocardial imaging agents are known as “cold spot” markers because they demonstrate decreased accumulation of activity in poorly perfused regions of myocardium.  CAD: Perfusion Tracer (SPECT) 27  Na+-K+ ATPase Pump: Potassium and its Analog (Ionic radius (Å) Tl+: 1.50; K+: 1.38; Rb+: 1.52 [201Tl+]Thallium: Production in cyclotron; γ-energy: 69-80 keV (very low, bad for SPECT); K+ analogue: monovalent; similar ionic radii.; Transported by Na+/K+-ATPase pump; Longer retention in myocardium than potassium; Fast blood clearance, T1/2(blood) = 3 min; Long half-life of 73 hrs; Decreased role in today’s clinical nuclear medicine. 99m Tc-Sestamibi (Cardiolite) and 99m Tc-tetrofosmin (Myoview); First- pass extraction lower than 201Tl+  CAD: Perfusion Tracer (PET 1) (82Rb+, [15O]H2O, [13N]NH3) 28 [82Rb+]Rubidium: [13N]NH3 16 O (p, α) 13N Half-life: 10 min; High image quality: Mean positron range: 0.492 MeV (Emax: 1.199 MeV), High extraction fraction in the K+ analogue: monovalent; Transported by Na+/K+-ATPase pump; myocardium: 80%, Long tissue retention → (Metabolic trapping Easily available: produced by generator; Short physical half-life with the conversion of NH3 to Glutamate and Glutamine by the of 75 s → multiple inj.; High β+-Energy (Emax: 3.3 MeV): low glutamine synthetase); On-site cyclotron is required; Uptake image resolution mechanism: Unclear, it is believed as: 1)Transported by Na+/K+- ATPase pump ([13N]NH4+) 2)Passive diffusion into the myocyte [15O]H2O ([13N]NH3); both forms in equilibrium in the blood, glutamine 14 N (d, n)15O; d = Deuterium (21H) synthetase activity is relatively constant over a wide range of metabolic conditions. Half-life: 2 min; Mean positron range: 0.735 MeV (Emax: 1.73 MeV); Nearly 100% first-pass extraction fraction → an ideal tracer for absolute measurement of myocardial blood flow; Uptake mechanism: Diffusion; On-site cyclotron is required; High background: required to delineate myocardium from blood pool  CAD: Perfusion Tracer (PET 2) ([18F]Flurpiridaz, Tacer comparison) 29 [18F]Flurpiridaz Myocardial Extraction of Perfusion Tracers pyridaben (pesticide) analog and binds to mitochondrial complex I with high affinity. Half-life: 110 min, allows exercise and pharmacological stress tests and permits cost-effective off-site production. Uptake mechanism: passive diffusion with very high first-pass extraction and slow washout from cardiomyocytes. Imaging: Is a promising investigational radiotracer for PET myocardial perfusion imaging, has favourable properties for quantification of myocardial blood flow (MBF). Imaging quality: 1)Tracer extraction efficiency from the blood to myocardium The ideal tracer is linear, therefore [15O]H2O is considered the 2)Tracer retention in myocytes (back-diffusion; trapped to gold standard for quantification of MBF. myocytes), clearance from the blood Other tracers show incomplete myocardial extraction from 3)Radioisotope arterial blood and curvilinear with increasing flow rates.  CAD: Metabolism Tracer 30 normal (left); Ischemic condition (left) Principles of [18F]FDG Metabolism → 18 F-FDG is the main PET agent used for myocardial viability studies 18 F-FDG is not a useful tracer of myocardial blood flow, because its uptake is not related to flow but to phosphorylation. There is 79.6% reduction in mortality for patients with viability treated by revascularization (p < 0.0001). PET myocardial viability imaging plays a significant role in risk stratifying patients with ischemic cardiomyopathy who may benefit from revascularization. Free Fat Acid (FFA)-Tracer IHA: metabolism to free Iodine → problem, toxic; IPPA: increased stability; BMIPP: Methyl stops beta- oxidation from happening, therefore stays longer in myocardial (SPECT)  CAD: Pump function Cardiac Tracers with metabolism graph 31 Imaging blood pools RBC (Red Blood Cells; erythrocyte) ∙ They are the most abundant (5 x 109/mL of blood) ∙ They are easy to be separated and handle in vitro ∙ They are not as dependent on energy and nutritional requirements as the others ∙ They display ease of labeling with radionuclide (99mTc, 51Cr, 111In, 68Ga) 99mTc-RBC Preparation In vitro kit method: Whole blood or red blood cells, Stannous Citrate (50 μg), 99mTc pertechnetate (TcO4--moves in and out of the RBC freely, reduced Tc could be trapped in RBC) In vivo method: 1) Sn (ll) injection, then 2) 99mTcO4-- Pro: requires only two injection and no blood handling Cons: poorer and irreproducible labeling efficiencies 99mTc-RBC Application ∙ Evaluation of cardiac function ∙ Detection of gastrointestinal bleeding ∙ Localization of hemangiomas ∙ Measurement of regional cerebral blood volume FDA approved Oncology [18F]-FDG 32  18 Tracer F-2-fluoro-2-deoxy-glucose ([18F]-FDG) Structure Cancer alteration Increased Glucose metabolism. Higher rate of glycolysis followed by lactic acid fermentation (even when enough oxygen is present), rather than by low rate of glycolysis followed by oxidation of pyruvate as in most normal cells. (Warburg effect) Therefore GLUT1 over-expression (on the surface of malignant cells) and high- rate phosphorylation by (overexpressed) hexokinase. Probably inhibition of mitochondrial uptake for normal ‘Krebs’ cycle. Uptake mechanism Via energy-dependent transmembrane transport proteins predominantly GLUT1 (and GLUT3) over-expressed on the surface of malignant cells. Tumor cells have increased intracellular hexokinase levels, which phosphorylate glucose and FDG. FDG-6-Phosphate is not further metabolized, therefore trapped in the cell Application/Indication Hodgkin's disease, non-Hodgkin's lymphoma, colorectal cancer, breast cancer, melanoma, and lung cancer.  Oncology [18F]-FCH and [18F]-FLT 33 Tracer [18F]-ethyl choline ([18F]FCH) Structure Cancer alteration Increased membrane or lipid synthesis Uptake mechanism Choline enters most cells using specific energy-independent cell membrane transporters (choline transporter). Upon entering the cell, choline is phosphorylated to phosphatidylcholine a reaction catalyzed by the enzyme cholinekinase(CK) Application/Indication Prostate carcinoma, esophageal carcinoma and neoplasms in the mediastinum-generally tumor with slow proliferation Tracer 3′-[18F]Fluoro-3′-Deoxythymidine ([18F]-FLT) Structure Cancer alteration Increased DNA synthesis Uptake mechanism Via nucleoside transporter; phosphorylation via thymidine kinase-1 (TK) to 18F-FLT-monophosphate and 18F-FLT-di/tri-phosphate via thymidylate kinase; more tumor specific than FDG Application/Indication Bronchus carcinoma, colorectal cancer, melanoma, gliomas  Oncology [18F]F-DOPA and [18F]-FET 34 Tracer [18F]-Dihydroxyphenylalanin([18F]F-DOPA) Structure Cancer alteration Increased amino acid transport and protein modification Uptake mechanism Via L-amino acid transporter (LAT1) and decarboxylated by the aromatic L-amino acid decarboxylase (AADC, DDC). Aromatic L-Amino Acid Decarboxylase (AADC, DDC) is upregulated in endocrine tumorc ells Application/Indication neuroendocrine tumors, neuroblastoma Tracer [18F]-O-2-Fluoroethyl-L-tyrosine ([18F]-FET) Structure Cancer alteration Increased amino acid transport and protein modification Uptake mechanism Via LAT1 transporter and is protonated within the cell. Amino acids analogues are substrate for the amino acid sodium-independent amino acid transport system L (LAT); LAT1 levels correlate with poor prognosis. FET is metabolically stable in vivo. It is not incorporated into proteins.The high uptake of FET in tumors is closely related to the upregulated proliferation (use of amino acids for protein synthesis as well as energy production) Application/Indication Bronchus carcinoma, colorectal cancer, melanoma, gliomas  Oncology [131I]-Iodide and [18F]FMISO 35 Tracer [123I] and [131I]-Iodide Cancer alteration Increased Ion transporter Uptake mechanism Via the sodium-iodide symporter (NIS) iodine enters the thyroid cell, is incorporated into monoiodotyrosine (MIT) by the Thyroperoxidase (TPO) and is ultimately stored in the thyroid follicles. Under the action of TSH (Thyreoidea- Stimulating Hormon) or TSH receptor autoantibodies, the uptake of iodine into the thyroid cells is increased. Application/Indication Autonome, multifocal and disseminiated adenom, Morbus Basedow, thyroid carcinoma, papillary and follicular thyroid carcinoma and struma Tracer [18F]Fluoromiso-nidazol ([18F]FMISO) Structure molecule in the cell: Increased Hypoxia (reduced oxygen level) Uptake mechanism Passive diffusion into cancer cells. Mechanism of reduction and intracellular retention of nitroimidazoles involves build-up of steady-state level of radical anions, which in absence of O2 produce intermediate that are highly efficient alkylating agent, RNH2, resulting in cellular retention of labelled tracer. Application/Indication hypoxic tumor region; often head and neck cancer, pancreatic carcinoma, glioblastoma etc.  Oncology Hydroxyapatite tracers CD20-targeting radiopharmaceutical 36  99m Tracer Tc/186Re-MDP*,Na18F, 153Sm-EDTMP,89Sr2+, 223Ra2+ Structure Phosphate (PO43-) analogues: 99mTc/186Re-MDP Hydroxy (OH-)analogue: Na18F Calcium (Ca2+) analogues: 89Sr2+;223Ra2+: Xofigo® (radiotherapy, α decay) Cancer alteration Increased Bone metabolism Uptake mechanism Tracers localize to hydroxyapatite Ca5[OH|(PO4)3] via interaction or exchange of phosphonate, hydroxy and of Ca2+; localization at sites where osteolytic, osteoblastic events take place. Application/Indication Bone metastases Tracer 111In/90Y-Ibritumomab tiuxetan (Zevalin) Cancer alteration Increased receptor expression Receptor/Antigen CD20 antigen Indication Follicular Non-Hodgkin lymphoma Uptake mechanism Specific binding to CD 20 antigen; > 90% of all B-cell non-Hodgkin's lymphoma cells express CD20. CD20 not expressed on hematopoietic stem cells, early B-precursor cells, mature plasma cells or in non-lymphoid tissue. Antigen is not stripped and not internalized after antibody binding. CD20 features stable, constant surface expression. Application/Indication Lymphomas are suitable for an antibody therapy, since they have a good blood supply and are easily accessible. Advantage over solid tumors is a decreased interstitial pressure and therefore good penetration. Indolent Lymphomas (eg, follicular germinal LymphomaI and II), aggressive lymphomas (eg diffuse large B-cell lymphoma), very aggressive lymphomas (such as B-lymphoblastic lymphoma precursor)  Oncology DOTATATE and PSMA 37  68 Tracer Ga-DOTATATE, 177Lu-DOTATATE (Lutathera©) Structure Theragnosis (68Ga as diagnosis) Cancer alteration Increased receptor expression Receptor/Antigen Somatostatin/somatostatin receptor Indication Neuroendocrine tumors, lymphoma, melanoma, breast cancer Uptake mechanism Somatostatin receptor subtype specific uptake and internalization Application/Indication Neuroendocrine tumors, melanoma, non-Hodgkin’s lymphoma 68 Tracer Ga-PSMA-11; 177Lu-PSMA-617(Pluvicto©) Structure Theragnosis (177Lu/225Ac as therapy) Cancer alteration Increased receptor expression Receptor/Antigen Prostate specific membrane antigen (PSMA) Indication Castration-resistant prostate cancer Uptake mechanism Folate hydrolase (FOLH1) called prostate specific membrane antigen (PSMA) PSMA is an integral membrane glycoprotein. It shows glutamate carboxypeptidase II (GCP-II) activity. It hydrolyses y-peptide bonds between N-acetylaspartate and glutamate Application/Indication PSMA expression increases progressively in:, Hormone-refractory Prostate cancer  Oncology Accumulation mechanism Cancer alterations and Theragnosis 38 Mechanisms of accumulation: Metabolism, Active transport, Passive diffusion, Absorption, Specific binding Molecular and functional alterations in cancer that are address with radiopharmaceuticals Theragnosis: Therapy & Diagnosis using one and the same targeting molecule but switching the radionuclide Major features of radiotracers used in the CNS (aka Target considerations) 39 Target density (Bmax) and localization The affinity for the target should be ideally in the nano-to picomolar range, depends on the Bmax (Bmax/Kd>10) Specificity/selectivity: High specificity and selectivity for the target to avoid off-target binding. Blood-brain barrier (BBB) penetration: Low non-specific binding. Ideal lipophilicity (LogD: 1-3) for small molecule. High molar activity: Important for low abundance targets. Metabolic stability: Radiometabolite NOT re-enter the brain. No substrate of efflux transporters such as p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) Structure attribute: Amendable for labelling with fluorine-18 or carbon-11. Targets (Bmax = total target density) with low expression levels (e.g. α-syn, a Parkinson marker) require a higher radiotracer affinity or selectivity, in order to show specific binding in vivo. Target concentrations are typically expressed in units of nM, mol/g, or mol/cm3 tissue. Bmax/Kd > 10 (rule of thumb) Kd: binding affinity (=Ki or IC50, means the same) Influence of affinity (Ki): Specific binding decreases as the affinity of the radioligand decreases Specific: binds to one specific target; Selective: binds to more than one target; Non-displaceable binding: the radiolabels binding to other sites then the target or free Lipophilicity: LogD 1-3; higher lipophilicity has increased BBB penetration and decreased specific binding (brain lots lipophilic) Specific activity and molar activity: The ratio of the radioactivity (GBq) to the total quantity (mg (specific), μmol (molar)) of radioactive plus non-radioactive molecules. Maximal specific activity (SAmax); 11C is diluted with 12C, 18F is diluted with 19F → important to have enough which bind to target to make signal and not all be occupied by non-radioactive compounds. Low abundance targets: Both compounds have the same affinity to the target and competitive binding to the target; Micro-dosing concept: to avoid pharmacological or toxicological effects 𝑅𝑎𝑑𝑖𝑜𝑎𝑐𝑡𝑖𝑣𝑖𝑡𝑦 𝑜𝑓 𝑙𝑎𝑏ⅇ𝑙𝑙ⅇ𝑑 𝑐𝑜𝑚𝑝𝑜𝑢𝑛𝑑 𝐺𝐵𝑞 𝑀𝑜𝑙𝑎𝑟 𝐴𝑐𝑡𝑖𝑣𝑖𝑡𝑦 = ( ) 𝑀𝑜𝑙ⅇ 𝑜𝑓 𝑟𝑎𝑑𝑖𝑜𝑎𝑐𝑡𝑖𝑣ⅇ 𝑝𝑙𝑢𝑠 𝑛𝑜𝑛 − 𝑟𝑎𝑑𝑖𝑜𝑎𝑐𝑡𝑖𝑣ⅇ 𝑚𝑜𝑙ⅇ𝑐𝑢𝑙ⅇ𝑠 𝜇𝑚𝑜𝑙 Which part of the molecule should be radiolabelled, so the labelled radiometabolite does not re-enter the brain, but if the radiotracer is a prodrug the radiolabel should remain on the metabolite, which then is the wanted radiotracer. Radiotracer should be not substrate of efflux transporters at the BBB such as p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) because therapeutic potential could be reduced when transported out of the brain. Mechanisms of exchange of molecules across the blood brain barrier (BBB) Applications of PET Imaging in CNS 40 Applications of PET Imaging in CNS  Pros and Cons C-11 C-11 production and strategies 41 Why C-11? Radiochemistry is a race against time ∙ Every molecule contains carbon and makes C-11 an “rules of thumb”: Three half-lives (60 min) is the ideal radionuclide. maximum time for synthesis, purification and quality ∙ Labelled molecule retains its biological properties. control. ∙ Large variety of chemical reactions possible. Required yields for 11C/18F PET tracers: ≥ 300 MBq ∙ Decay characteristics: 98.1% β+, T1/2 = 20.4 min C-11 Preparation: C-11 and [11C]CO2 are produced in a ∙ Repeated PET studies in same individual. cyclotron ∙ Multi step synthesis possible (maximum ~1 h total synthesis time) ∙ Low radiation burden to patients/volunteers. Challenges and drawbacks: ∙ Need ‘in-house’ cyclotron and advanced lab facilities ∙ Sometimes half-life is too short for synthesis and PET application Strategies for 11C-based radiosynthesis ∙ Introducing the C-11 atom as late as possible in the reaction sequence ∙ Minimizing the synthesis time to optimize radiochemical yield and molar activity ∙ Minimizing isotopic dilution Features of radiochemistry: Specific/Molar activity, Stoichiometry, Radiolabelling position [11C]methylation reactions 42 Why [11C]methylation? ∙ Many lead compounds for PET tracers contain methyl functionalities. ∙ Precursor molecules can be synthesized, analogous to reference compounds. ∙ Reliable methods to synthesize carbon-11 labelled methylating reagents. ∙ Often very high yielding reactions in short synthesis time. ∙ Minimal side product formation. Example for methylation are kinase inhibitors Methylation reactions with [11C]methyl iodide is the most frequent used method for 11C-radiolabeling The methylation is generally carried out on N-, O and S nucleophiles [11C]CH3OTf is synthesized by passing [11C]CH3I through a silver triflate column at 200°C [11C]CH3OTf more reactive; shorter reaction times, lower reaction temperatures Thioflavin T binds Aβ plaques and [11C]PIB is an radioactive analogon. [11C]CO2 reactions 43 [11C]CO2 Chemistry: Using Grignard Reagent Challenges: Low specific activity (CO2 from the air). Quality of Grignard reagents. Functional group tolerability  F-18 production Reaction summary 44 Pass through ion exchange cartridge, recover [18O]water and “trap and release” [18F]fluoride ion with 2K+CO32-/K222 or Bu4N+OH- (to [18F]/KF/K222 or [18F]TBAF). K222 forms a strong complex with K+, leaves 18F-fluoride ion exposed (naked). Eluted [18F]fluoride is in aqueous phase, it is strongly hydrated and inactivate for nucleophilic reactions, therefore it needs 1) phase-transfer catalysts; 2) azeotropic drying with acetonitrile. Aliphatic Nucleophilic 18F-Substitution 45 Aliphatic Nucleophilic 18F-Substitution: SN2 mechanism Pseudo-first-order reaction kinetics LG (leaving group): Cl, Br, I, tosylate, mesylate, nosylate, triflate M+: Cs, Rb, R4N, K/K222 Solvent: acetonitrile, DMF, DMSO What is Boc? tert-Butyloxycarbonyl, a protecting group [18F]florbetapir is used to image β-amyloid Other examples: [18F]FMISO, [18F]FET, [18F]Flurpiridaz, [18F]FE- PE2I, [18F]FLT Aromatic Nucleophilic 18F-Substitution 46 Aromatic Nucleophilic 18F-Substitution: SNArMechanism EWG (Electron-withdrawing group): NO2, CN, CHO, COR, COOR LG: (F), Br, I, NO2, (CH3)3N+ M+: Cs, Rb, R4N K222/K Solvent: DMSO, DMF Aromatic Nucleophilic 18F-Substitution: Activated Aromatic Rings → [18F]FDOPA is special (no aromatic nucleophilic substitution, but 2 ways possible) Electrophilic 18F-Labeling: Radiosynthesis of 6-[18F]F-DOPA via 18F-fluorodemetallation reactions: Copper Mediated Radiofluorination: Neurology: Brain cuts CNS tracers list 47 Nuclear Imaging: in the brain, neurology rat MRI is precise, can determine the different regions → FDA approved Neurology Dopaminergic System Available Radiotracers 48 Available Radiotracers We don’t radiolabel dopamine cause it doesn’t penetrate the BBB. It can only be synthesised in the presynaptic neuron. Dopamine is involved in many physiological and behavioral processes including: cognition, locomotion, mood, motivation, and reward. Abnormalities in the central dopaminergic systems contribute to several neuropsychiatric diseases, including: Parkinson’s disease, dementia with Lewy-bodies (DLB), schizophrenia, bipolar disorder, binge eating disorder, and addiction. Neurology Dopaminergic System Dopamine synthesis: [18F]FDOPA D2 Receptor: [11C]Raclopride 49 [18F]FDOPA: Dopamine Synthesis (AADC) [18F]FDOPA: 1) Derivative of anti-parkinsonian drug L- DOPA (Levodopa); 2) measurement of amino acid decarboxylase activity (AADC); 3) assessment of presynaptic dopaminergic function. Carbidopa (CD): a peripheral AADC inhibitor (L-DOPA stays longer in cell, longer therapeutically active) Embryonic dopamine cell transplantation to treat Parkinson’s disease where the stratum region is reduced, imaging with [18F]FDOPA AADC decarboxylases [11C]FDOPA therefore the radiolabel placement is important (not the carboxyl C because it gets cleaved, but the C binding to the ring which stays trapped in the cell) {Radiometabolites!} [11C]Raclopride: Measure Dopamine Changes (like amphetamine (cocaine) abuse) The administration of amphetamine produces a large increase in endogenous dopamine. D2 receptor availability is significantly decreased across a wide variety of types of drug addictions, whereas the decreases are observed both during early drug withdrawal and after protracted drug detoxification.  Neurology Dopaminergic System DAT Transporter: [123I]FP-CIT & [18F]FE-PE2I 50 Dopamine Transporter (DAT) Tracers Removed the COO in the cocaine between the two rings because it’s unstable, gets cleaved really fast and has a short half-life → stabilised radiomolecules ([123I]FP-CIT & [18F]FE-PE2I). Labelling of [123I]FP-CIT: para of ring not good enough EWG for aromatic nucleophilic substitution, therefore same special way like [18F]FDOPA (2 ways) used for labelling. DaTScan: SPECT findings in neurodegenerative parkinsonian syndromes A) Typical “dot-shape” reduction in the tracer uptake in idiopathic Parkinson’s disease (iPD); B) A more diffuse “balanced” loss in a patient with dementia with Lewy Bodies; C) A more symmetric involvement in early stages of Progressive Supranuclear Palsy (with early involvement of caudatus); D) A markedly asymmetric reduced uptake (involving both putamen and caudate) in a patients with Corticobasal degeneration.  Neurology Monitoring AD Metabolism Tracer [18F]FDG 51 Cerebral glucose metabolism is closely associated with synaptic Regional Glucose Metabolism function and density Cerebral glucose hypometabolism is a suitable marker to detect neuronal dysfunction. The extent of metabolic impairment predicts cognitive decline and is closely related to disease severity Principles of [18F]FDG Metabolism (Uptake via GLUT1 and trapped by phosphorylation trough the hexokinase). In the brain the main energy source is glucose! The pathway doesn’t change from the healthy to the diseased cells, but there metabolism can change. (Perfusion changes parallel glucose metabolic changes in neurodegeneration) Metabolism Tracer [18F]FDG for AD Imaging 18 F-FDG-PET in AD shows typical areas of hypometabolism in posterior cingulate, parietotemporal, and temporomesial cortices. However, ¹⁸F-FDG-PET cannot provide information on Frontotemporal Dementia (FTD) occurs when nerve cells in the neuropathology underlying the metabolic abnormality frontal and temporal lobes of the brain are lost. The behavioral variant-type FTD has been specifically related to hypometabolism of the right inferior frontal lobe. Neurology: Alzheimer’s Disease (AD) Misfolded proteins, tracers summary 52 Hallmarks of Alzheimer’s Disease: Beta amyloid: deposits outside cells and in blood vessels of the brain → activate microglial cells → release of inflammatory mediators and might contribute to synapse loss by building β- amyloid plaques. Tau: misfolded tau → neurofibrillary tangles inside neurons; tau can pass through synapses to other neurons. Neurology: Alzheimer’s Disease (AD) Misfolded proteins (Beta-amyloid) 53 Amyloid PET Tracers [18F]flutemetamol and [11C]PIB compare the same, but F-18 has a longer half-life which is a pro. [18F]Florbetapir for Imaging AD Brain Amyloid plaque reduction with Aducanumab (new approved antibody to treat Alzheimer disease, less plaque after treatment) Neurology: Alzheimer’s Disease (AD) Misfolded proteins (Tau) 54 Available Tau Tracers Second generation is improved to the first generation. Representative [18F]flortaucipir(FTP) (less selective) and [18F]RO948 images for two patients with AD dementia, and one healthy control Comparison of SUVR of [18F]flortaucipir (FTP) and [18F]RO948 in ROIs covering typical sites of [18F]flortaucipir off-target binding ( or target selectivity) regions 55 56