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Molecular Imaging

Molecular Imaging. Molecular imaging is a new discipline that helps understanding complex pathological processes by visualizing unique molecular signatures at the cellular, subcellular or gene level. This technique Contributes diagnosis of cancer, neurological and cardiovascular diseases

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Molecular Imaging

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  1. Molecular Imaging • Molecular imaging is a new discipline that helps understanding complex pathological processes by visualizing unique molecular signatures at the cellular, subcellular or gene level. • This technique • Contributes diagnosis of cancer, neurological and cardiovascular diseases • Also contributes to shorten the time for developing new medicine at lower cost • Is expected to have a major economic impact due to earlier and more precise diagnosis • Among imaging modalities, numerous studies have been made with PET. However, complementary development of PET and SPECT is required for widespread applications of this technique.

  2. The first artificially produced element with no stable isotopes A transitional metal belongs to the second transition series Its chemistry is close to that of rhenium Tc 99m 43

  3. Is obtained by a generator system utilizing a radiation equilibrium between 99Mo and 99mTc Emits a -ray of 140 keV with a half-life of 6 h, which is suitable to SPECT imaging Tc 99m 43 The most widely applied radionuclide in diagnostic nuclear medicine

  4. 90Mo-99mTc Radiation Equilibrium β--Decay， T1/2 = 65.9 h 99Mo 99mTc Radiation Equilibrium Nuclear Isomer Transition g-ray (140 keV) T1/2 = 6 h 99Tc 99Ru β--Decay， T1/2 = 2.1 x 105 y （Stable）

  5. 99Mo - 99mTc Generator System Generation of 99mTc from 99Mo 100 Decay Curve of 99Mo Max 99mTc Radioactivity (%) 10 1 0 1 2 3 4 5 Days Separation of 99mTc from 99Mo Vacuum Vial Saline Alumina Column 99MoO42-/ 99mTcO4- Only 99mTc is eluted from the column

  6. Is obtained by a generator system utilizing a radiation equilibrium between 99Mo and 99mTc Emits a -ray of 140 keV with a half-life of 6 h, which is suitable to SPECT imaging Tc 99m 43 The most widely applied radionuclide in diagnostic nuclear medicine

  7. Advantage of SPECT over PET The resolution of PET (Positron Emission Tomography) is affected by positron range PETrecognizes the site of positron annihilation SPECT (Single Photon Emission Computed Tomography) recognizes the sites of tracer accumulation PET tracer SPECT tracer Positron Range Impairs resolution of PET

  8. SPECT Images 99mTc-MIBI Mouse Heart Fused Images 123I-IBZM Moue Brain D2 Receptor

  9. Simultaneous Dual Isotope Imaging of PerfusionandDopamine D2 Receptorsin Rat Brain MRI 99mTc-HMPAO MRI 123I-IBF SPECT allows simultaneous images of cerebral blood flow and D2 receptor function Images co-registered with MRI

  10. SPECT/CT Images（Murine Thyroid） • 99mTcO4- (50-80 μCi) • 6 h post-injection Multi pinhole Radius of gyration: 35 mm Acquired for 10 min (360 degree) Single pinhole Radius of gyration: 25 mm Acquired for 20 min (360 degree)

  11. 99mTc Radiopharmaceuticals in the 70’ • Reticuloendothelial System • 99mT-Sn colloid • Hepatobiliary excretion • 99mTc-HIDA • Renal Function • 99mTc-DTPA • Bone Function • 99mTc-MDP At the initial stage of 99mTc radiopharmaceutical development, it was thought that Tc is a foreign substance and is recognized as such by the body

  12. T T c c O OH2 R OH2 OC Tc Breakthrough in Tc Chemistry Tc CO OH2 OC OC CO CO Representative Tc Complex Tc Core HN NH O NH N O TcO(V)3+ N N S S O O H TcN(V) 2+ + Tc(I)+

  13. O Tc T c N N N N O O H Chemical Design of 99mTc-Labeled Compound for Cerebral Blood Flow Measurement Structural modification HN NH O N N O O H GSH can easily attack the Tc center • Neutral, compact and lipophilic complex that penetrates intact BBB • No retention in the brain Rapid conversion to a hydrophiliccompound in the brain

  14. O Tc NH COOEt N EtOOC T c S S Chemical Design of 99mTc-Labeled Compound for Cerebral Blood Flow Measurement Structural modification N NH O S S The properties of the 99mTc complex (stable, neutral and lipophilic) are masked so that the pharmacokinetics is governed only by the functional groups • Neutral, compact and lipophilic complexes that penetrates intact BBB • No retention in the brain Rapid hydrolysis of an ester group to generate a hydrophiliccompound

  15. O S S Tc N N Chemical Design of 99mTc-Labeled Probes（Dopamine Transporter） SPECT Probe 123I-Cocaine 123I H C 3 PET Probe C l O C O O C H 3 O N N N Tc S S F 11C-Cocaine Cocaine • The chemical structure of 99mTc-labeled cocaine analogs differs significantly from that of cocaine • These compounds still possess substrate specificity to dopamine transporter of the brain

  16. 99mTc-Labeled Probe for Assessing Fatty Acid Metabolism in the Heart 123I O H O C H O 15-(p-[123I]iodophenyl)pentadecanoic acid ([123I]IPPA) O T c O C C O C O Transported and recognized as a substrate for b-oxidation by the myocardium O H O J. Med. Chem. 50 (3), 543-549, 2007 [11C]palmitic acid

  17. Present Design of 99mTc-Labeled Probes Tc Tc Divalent Complex Divalent Ligand 99mTc-Labeled Probe(10-7 M) ：Targeting unit Complexation Monovalent Complex Monovalent Ligand Tc Avidity Tc (10-7 M) Ligand (10-4 M) • Conjugate a chelating molecule with a targeting unit (e.g., tropane, peptide) • A large excess ligand is used to obtain 99mTc labeled compound with high • radiochemical yields in short reaction times • Divalent ligands provide divalent 99mTc complexes that possess higher • avidity to target molecule than monovalent counterpart

  18. c ( R G D f K ) c ( R G D f K ) H N O O N H O O 5 5 N N H O O H S H H S 99mTc-Labeled RGD Peptides for Tumor Imaging c ( R G D f K ) c ( R G D f K ) H N O O N H O 5 5 O N N O H Tc S S O O Divalent RGD Ligand Divalent 99mTc-Labeled RGD

  19. SPECT Images Non purified 99mTc-TMEC-RGD2(contained 10-4 M ligand) HPLC-Purified 99mTc-TMEC-RGD2 (No excess ligand) Tumor (U87MG cells）

  20. Problem Tc Tc Tc Capillary Wall Target (peripheral) Blood ：99mTc-labeled probes ：Ligand The presence of excess ligand impairs the accumulation of 99mTc labeled probes inthe target

  21. Dilemma • Excess ligands are used to prepare 99mTc-labeled probes in order to achieve high radiochemical yields in short reaction times • The presence of excess ligands reduces target accumulation of 99mTc-labeled probes by competing for the target molecule • Removal of excess ligands from the 99mTc-labeled probes by HPLC or solid-phase extraction method is possible • HOWEVER, such manipulation impairs the advantages of 99mTc-labeled probes • simple and sterile preparation • loss of 99mTc-labeled probes during the purification process (HPLC separation, evaporation and reconstitution) • ANY OTHER APPROACH ?

  22. Preparation of 99mTc-Labeled Probes 99mTcO4- Kit （Ligand + SnCl2) 99mTc-Labeled Probe

  23. Dilemma • Excess ligands are used to prepare 99mTc-labeled probes in order to achieve high radiochemical yields in short reaction times • The presence of excess ligands reduces target accumulation of 99mTc-labeled probes by competing for the target molecule • Removal of excess ligands from the 99mTc-labeled probes by HPLC or solid-phase extraction method is possible • HOWEVER, such manipulation impairs the advantages of 99mTc-labeled probes • simple and sterile preparation • loss of 99mTc-labeled probes during the purification process (HPLC separation, evaporation and reconstitution) • ANY OTHER APPROACH ?

  24. New Chemical Design of 99mTc-Labeled Probes • Change the paradigm from “Development of 99mTc-labeled probes that provide information similar to those by PET or Radioiodinated Compounds” to “Development of radiolabeled probes that can be best achieved by using 99mTc” that is • 99mTc-labeled probes utilizing chemical properties of Tc, the properties as a transitional metal

  25. New Concept for Designing 99mTc-Labeled Probes Tc Tc Tc Divalent Complex Tracer amount Monovalent Ligand 10-5 – 10-4 M Tc Trivalent Complex Tracer amount • Synthesis of multivalent (divalent or trivalent) 99mTc- • labeled probes from monovalent ligand • The target accumulation of 99mTc-labeled probes would be less impaired by the presence of excess ligands

  26. Rationale behind the Chemical Design 99mTc Target 99mTc 99mTc Divalent 99mTc-labeled probes exhibit higher avidity than monovalent ligands to target Blood Higher target accumulation

  27. 99mTc 99mTc Higher Retention 99mTc 99mTc 99mTc 99mTc 99mTc Target 99mTc 99mTc Rationale behind the Chemical Design 99mTc Divalent 99mTc-labeled probes exhibit slower dissociation from target than monovalent ligands Blood No dissociation Dissociation

  28. Validation of the Chemical Design O c ( R G D f K ) c ( R G D f K ) O 5 H N O O N H NH HN-c(RGDfK) HO O 5 5 O N H H N SH O H Tc S S O O c ( R G D f K ) c ( R G D f K ) c ( R G D f K ) c ( R G D f K ) H N O O N H H N O O N H O O 5 O 5 5 5 N N O N N H O O H O H Tc S H H S S S O O Monovalent Ligand Divalent 99mTc Complex 99mTc(V)-GH Divalent 99mTc Complex Divalent Ligand

  29. Multivalent 99mTc-Labeled Probes

  30. Mixed Ligand [99mTc(CO)3(OH2)3]+ Compound Trivalent Compound Divalent Compound with pharmacokinetic modifier (R’) M: Tc/Re R: Targeting Unit

  31. Synthesis of 99mTc-Labeled RGD Peptide CN-Hx-c(RGDfK) Divalent compound M: 99mTc/Re

  32. SPECT Images • 99mTc-(CN-Hx-RGD)2 (300 µCi) • 2 h post-injection Tumor Multipinhole Radius of gyration: 25 mm. Acquired for 20 min (360 degree)

  33. Synthesis of 99mTc-Labeled RGD Peptide CN-Hx-c(RGDfK) Divalent compound CN-EG3-c(RGDfK) Trivalent compound M: 99mTc/Re High hepatic accumulation

  34. Conclusions • The monovalent penicillamine derivatives provided divalent99mTc-labeled compounds in high yields • The pharmacokinetics was manipulated by changing linkage structures between penicillamine and c(RGDfK) • The divalent 99mTc-[Pen-SSG-c(RGDfK)]2 • visualized tumor in mice by SPECT/CT without removing excess ligands • The use of 99mTc(CO)3(OH2)3 core provided divalent or trivalent99mTc-labeled compounds in high yields • The pharmacokinetics was also manipulated by changing linkage structures between CN and c(RGDfK) • The present chemical design of 99mTc-labeled multivalent compounds would constitute a new strategy to develop molecular probes for SPECT

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