Programme Overview Session: ES 01

Learning Objective

-general characteristics of the molecular structure of probes for radionuclide imaging comprising the vector-linker-radionuclide principle
-general characteristics of vector molecules (small molecules, peptides, proteins, cells, nanoparticles)
-basic radiochemical methods to radiolabel vector molecules with carbon-11, fluorine-18 and radio-iodine

Content

Radionuclide imaging provides quantification of the radionuclide concentration as a function of time after administration.
The radioactive probe consists of a radionuclide coupled to a vector.  The biological characteristics of the vectormolecule result in an increased concentration of the radionuclide probe in the target cells, tissues or body fluids compared to the surrounding tissue resulting in the image contrast. This may be based on physical characteristics of the vector or on high-affinity interactions of the vector with its target coupled with clearance of the vector from non-targetted tissues.
Radionuclides for molecular imaging have relatively short half-lifes and are only present in very small mass amounts.  In contrast to chelation chemistry that is applied for radiometals, coupling of carbon-11, fluorine-18 or radio-iodine to the vector generally requires formation of a covalent bond between the radionuclide and the target by using organic (radio)chemistry methodology. To minimize exposure of radiochemists to ionizing radiation, radiochemical reactions including purification and formulation for intravenous injection are automated by use of synthesis modules that are placed in lead-shielded hotcells.

Relevant Publications

• Design and Challenges of Radiopharmaceuticals. Vermeulen K, Vandamme M, Bormans G, Cleeren F. Semin Nucl Med. 2019 Sep;49(5):339-356. doi: 10.1053/j.semnuclmed.2019.07.001.
• An Overview of PET Radiochemistry, Part 1: The Covalent Labels ¹⁸F, ¹¹C, and ¹³N.  Pichler V, Berroterán-Infante N, Philippe C, Vraka C, Klebermass EM, Balber T, Pfaff S, Nics L, Mitterhauser M, Wadsak W. J Nucl Med. 2018 Sep;59(9):1350-1354. doi: 10.2967/jnumed.117.190793. Epub 2018 Jul 24.
• J Lewis, A Windhorst, B Zeglis (Eds.), Radiopharmaceutical Chemistry Springer 2019

Learning Objective

•To present an overview on radiometal-based PET and SPECT tracers and how chelation chemistry is important
•To describe clinically used radiometal-labeled PET and SPECT agents
•To discuss emerging radiometal-labeled agents in the pre-clinical space

Content

Radiometals are very important in the fields of radiopharmaceutical chemistry and nuclear medicine, and they span the periodic table ranging from Sc-44 to Ac-225.  This presentation will focus on selected radiometals that are used clinically or are established in pre-clinical and/or human studies (Ga-68, Cu-64, Zr-89 for PET imaging; Tc-99m, In-111, and Lu-177 for SPECT imaging).  The chemistry of radiometals requires an understanding of coordination chemistry and how to design chelators for stable complexation in vivo.  Radiolabeling chemistry considerations include minimizing trace metal contamination and choosing the best buffer systems and pH.  Choosing chelators will depend on several factors such as the hard/soft characteristic of the metal, the preferred oxidation state, and the lability of the radiometal towards dissociation to protein binding in vivo.  The preferred coordination environment for radiometals will greatly affect the biodistribution of a chelator-peptide conjugate.  Cell surface receptors and enzyme inhibitors are often upregulated on tumors and are a common target for designing radiotracers for imaging and therapy.  Radiometal-based agents targeting somatostatin receptor and prostate specific membrane antigen (PSMA) will be described, including different chelator choices made based on optimizing target uptake with fast non-target organ clearance.  The chelation chemistry of Zr(IV) will also be included and a novel chelator system under investigation will be described for immunoPET and radioimmunotherapy.

Relevant Publications

Learning Objective

This Education Talk will highlight some of recent progresses in the small molecule organic fluorophores, innovative design strategies and fine-tuning of optical properties. In particular, an emphasis is placed on trigger-responsive probes, detecting enzyme activity or cellular metabolites. Viewers will learn about variety of possibilites in the development of optical probes suitable for required applications.

Content

Light-based imaging modalities are of high importance in the field of medical imaging, in particular those based on fluorescence and photoacoustic, as they enable very sensitive and fast imaging at  high resolution. For fluorescence imaging, probes emitting a large number of photons per excitation event are most suitable, while for photoacoustic non-emitting compounds are preferred; nevertheless, in both cases chromophores exhibiting absorption / emission in tissue-transparent window (near infrared, NIR) are needed. Therefore, this talk highlights few recent developments towards such NIR-probes.
- The novel (fluorophores and quenchers) probes
- Probe design strategies for detecting short lived species, metabolites and enzymes
- Bioimaging applications

Relevant Publications

1) J. Am. Chem. Soc. 2019, 141, 2770
2) Angew. Chem. Int. Ed. 2019, 58, 6911
3) Angew. Chem. Int. Ed. 2019, 58, 12415
4) Acc. Chem. Res. 2018, 51, 2897
5) J. Am. Chem. Soc. 2019, 141, 19226

Learning Objective

After completion of this lecture, participants are aware of:

• The basic concepts of relaxation in nuclear magnetic resonance
• The main mechanisms underlying paramagnetic relaxation
• The structure/properties relationship of MRI contrast agents
• The potential advantages, challenges, and caveats of the MRI approach to molecular imaging

Content

• Relaxation in Magnetic Resonance Imaging (MRI): T₁ and T₂ weighted MR images
• Physical principles underlying paramagnetic relaxation: the relaxivity
• Main contributions to relaxivity: electronic relaxation, water exchange, hydration number, molecular tumbling, second sphere and outer sphere
• Gadolinium chelates as contrast agents for MRI: extravasation and blood pool agents
• The issue of gadolinium release and accumulation in vivo
• Microenvironment responsive agents: pH, redox, enzymes
• Approaches to molecular imaging by targeted MRI contrast agents

Relevant Publications

A. Merbach, L. Helm, É. Tóth (Eds) “The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging, Second Edition”, 2013, John Wiley & Sons, Ltd

S. Aime, M. Botta, E. Terreno. Gd(III)-based contrast agents for MRI. Adv Inorg Chem 2005; 57: 173–237

P. Caravan, J.J. Ellison, T.J. McMurry, R.B. Lauffer. Gadolinium(III) Chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev 1999; 99: 2293–2352

V. Catanzaro, C.V. Gringeri, V. Menchise, S. Padovan, C. Boffa, W. Dastrù, L. Chaabane, G. Digilio, S. Aime, A R_2p/R_1p Ratiometric Procedure to Assess Matrix Metalloproteinase-2 Activity by Magnetic Resonance Imaging. Angew. Chem. Int. Ed. 2013, 52, 3926 –3930

S. Aime, M. Botta, D. Esteban-Gómez & C. Platas-Iglesias. Characterisation of magnetic resonance imaging (MRI) contrast agents using NMR relaxometry. Molecular Physics 2019, 117(7–8), 898–909