Radiochemistry Program Research Projects
The overall research goal of the Radiochemistry Program is to synthesize novel positron emission tomography (PET) labeled compounds and radiopharmaceuticals for preclinical and clinical evaluations.
Our program has several active areas of research including:
- Advanced Radiochemical Reactions with [18F]fluoride: Iodonium Ylide Mediated Fluorination
- Advanced Radiochemical Reactions - 11C-Carbonylation Chemistry
- Multi-Step Chemistry with Short-Lived Radionuclides - "Total Radiosynthesis"
- Flow Radiochemistry - Microfluidic Platform
- Radiotracer development for Monoamine Oxidase B
- New Approaches for Neuroimaging, particularly in Alzheimer's Disease
- Solid-Metal Targetry and Metal Radionuclide Production
- Ligand Design and Synthesis
- Pathway Imaging and Radiotracer Evaluation in vivo
- Development of PET Radiopharmaceuticals for Routine Clinical Use
Fluorine-18 (t½ = 109.7 min) is the most commonly used isotope to prepare radiopharmaceuticals for molecular imaging by positron emission tomography (PET). Nucleophilic aromatic substitution (SNAr) reactions of suitably activated (electron-deficient) aromatic substrates with no-carrier-added [18F]fluoride ion are routinely carried out in the synthesis of radiotracers in high specific activities. Despite extensive efforts to develop a general 18F-labelling technique for non-activated arenes there is an urgent and unmet need to achieve this goal. Here we describe an effective solution that relies on the chemistry of novel spirocyclic hypervalent iodine(III) complexes which serve as precursors for rapid, one-step regioselective radiofluorination with [18F]fluoride. This methodology proved to be efficient for radiolabelling a diverse range of non-activated functionalized arenes and heteroarenes, including arene-substrates bearing electron-donating groups, bulky ortho functionalities, benzylic substituents and meta-electron-withdrawing groups. Polyfunctional molecules and a range of previously elusive 18F-labelled building blocks, compounds and radiopharmaceuticals were synthesized. We have recently demonstrated that this methodology is suitable for the production of a PET radiopharmaceuticals and validated it for human use.
Carbon-11 chemistry, like organic synthesis, is rich with potential starting materials and synthetic intermediates such as [11C]CH3I, [11C]CO and [11C]COCl2 etc. However, the standard cyclotron production of 11C using the 14N(p,α)11C transmutation reaction on a gas-phase target generates [11C]CO2 which is subsequently converted to other reactive intermediates. Given the short half-life of 11C (t1/2 = 20 min.), significant advantages in terms of overall yield and increased specific activity of 11C-radiotracers could be achieved by using the [11C]CO2 directly from the cyclotron as the primary reagent for radiolabeling. Our work in this field centers on the use of 11C-carbonylation chemistry for rapid installation of a 11C atom in a diverse array of carbonyl-based functional groups including carboxylic acids, carbamates, ureas and oxazolidinones.
Traditional radiochemical methods for incorporating relatively short-lived radionuclides such as 11C (t1/2 = 20 min.) or 18F (t1/2 = 109.7 min.) typically employ reactions which aim to introduce the radioactive atom in a step which is close to the final product with minimal chemical transformations performed in the radioactive setting. A significant challenge in radiochemistry is the limited choice of labeled reagents (or building blocks) available for the synthesis of novel radiopharmaceuticals. Limitations in building-block chemistry mean that most drugs cannot be labeled with 11C or 18F due to a lack of efficient and diverse radiosynthetic methods. Our approach of multi-step “Total Radiosynthesis” addresses many issues by allowing us to construct complex organic molecules from basic radiolabeled building-blocks. Key to the success of our strategy is the use of efficient, rapid, high-yielding reactions coupled with advanced automated technologies which allows us to radiolabel drug molecules (often in unique positions) that cannot be labeled with traditional methods. Examples of successful and versatile multi-step radiochemistry with 11C-acid chloride and 18F-fluoroaniline building blocks are shown.
Microfluidic technology (a.k.a. lab-on-a-chip) is the miniaturization of components and equipment and recently has emerged as a powerful tool in PET radiochemistry. A basic microfluidic device may include enclosed micro-channels, simple mixing units, a heat source and a pumping system to control fluid or gas flow. Key advantages of flow chemistry on the micro-scale is that reaction conditions such as time, temperature, pressure, reagent concentrations and mixing efficiency etc can be controlled precisely, thus improving the reliability and reproducibility of many chemical transformations. Other advantages of microfluidics for radiochemistry include the ability to use more forcing conditions to drive reactions toward completion. In our experience with the Advion NanoTek microfluidics system investigating the production of more than 80 11C and 18F radiotracers, we have demonstrated higher radiochemical yields, increased specific activities, reduced reaction times and increased consistency in terms of successful radiopharmaceutical production compared to standard non-flow conditions in reactor vials. A further advantage flow chemistry is the ability to combine multiple synthesis and purification modules into one seamless machine. For example, our recent work has led to the first demonstration of in-line fluorination reactions using the Advion NanoTek, with flow hydrogenation on the ThalesNano H-Cube and product purification using the high-performance liquid chromatography (HPLC) capabilities of the GE TRACERlab FXN. We also applied this technology to the radiosynthesis of radiopharmaceuticals, including [18F]FPEB and [18F]T807, which demonstrated the first radiotracers that prepared via microfluidic flow chemistry for human use.
Preclinical and human genetic work link dysregulated monoamine oxidase (MAO) activity to psychiatric illnesses including substance abuse, and neurodegenerative diseases. MAO is the principle enzyme for metabolizing endogenous amine neurotransmitters such as dopamine, serotonin, and 2-phenylethylamines, and is a metabolic barrier to protect neurons from exogenous amines. Among the two isoenzymes, MAO-A and MAO-B, the latter is primarily expressed in the basal ganglia and has been a significant target for drug development and molecular imaging with PET. PET radiotracers for MAO-B have been avidly pursued, including the selective and irreversibly binding (suicide-inhibitor) [11C]L-deprenyl-D2 and dozens of 11C-, 18F-, and 123I-labeled analogs which have not been translated for human use. Enabled by [11C]CO2 fixation methodology to label at the 11C-oxazolidinone carbonyl group, the first reversible MAO-B radiopharmaceutical, [11C]SL25.1188, has been translated to humans. We have are actively developing new radiotracers for this important neuropsychiatric target for imaging patients suffering from addictions and neurodegenerative diseases.
Alzheimer's Disease (AD) is the most prevalent form of dementia yet our understanding of the etiology of AD, and many of the biochemical and physiologic changes that occur on disease progression remain largely unknown. Given the technical difficulties of identifying and diagnosing patients at pre- or early-AD stages, it is unsurprising that non-invasive imaging of AD patients with positron-emission tomography (PET) or single-photon emission computed tomography (SPECT) using radiotracers targeting various biomarkers or “hallmarks” of the disease has led the way in probing the pathobiology of AD. The most common clinical biomarker of AD is the presence of amyloid-b protein aggregates in brain tissue, referred to as Ab-plaques. While the amyloid cascade hypothesis remains the most prominent stimulus for research on the development of both radiotracers and chemotherapeutic treatments of AD, numerous other hypotheses and mechanisms have been proposed.
Solid-Metal Targetry and Metal Radionuclide Production
This project centers on our efforts to advance the 16.5 MeV GE PETtrace cyclotron as a new solid-target platform for accessing promising positron-emitting and Auger emitting radionuclides. Our efforts focus on establishing optimized irradiation conditions for generating clinically relevant quantities of various radionuclides including 89Zr etc. We are also exploring new methods for reliable and simplified isolation of chemically useful forms of various metal radionuclides that will facilitate further radiochemistry and application in radiotracer development.
We are working closely with various groups including Dr. Ivan Greguric at the Australian Nuclear Science and Technology Organization (ANSTO; Sydney, Australia) to synthesize and evaluate new chelates with improved potential to stabilize high-valent metal ions via changing the coordination geometry.
This project concentrates on evaluating the use of PET radiotracers to provide biochemical readouts of changes in cellular signaling upon disease progression and treatment. The concept of Pathway Imaging is to step beyond using imaging agents for merely mapping target density and use imaging to follow temporal (pharmacodynamics) changes in tissue/cellular signaling processes that occur on intervention to provide a non-invasive measure of patient response to therapy and to assess drug efficacy before gross anatomic changes occur.
Production Radiochemistry Team
Back row left to right: Peter Rice, Gary Siwruk
Front row left to right: Raul Jackson, Dan Yokell, Neil Vasdev
In Summer 2010, MGH completed a comprehensive renovation and major expansion of the PET Radiochemistry and PET Nuclear Pharmacy, including a new cyclotron. We have several radiotracers in routine clinical use for neurology, cardiology and oncology. Our state-of-the-art facility is staffed with a laboratory Manager (Dan Yokell, PharmD, RPh) working closely with several production radiochemists and radiopharmacists.
The Major Equipment used by the facility includes:
- GE PETtrace 18/9 MeV Dual Particle Cyclotron
- Fully equipped and staffed cyclotron support facilities
- cGMP Compliant manufacturing facility and clean room housed within the PET Nuclear Pharmacy
- 3 Hot Cells, 14 Mini Cells
- Shielded ISO Class 5 Isolator
- 2 FDG Automated chemistry modules
- 2 GE FX-N F-18 Automated chemistry modules
- 2 GE FX-C C-11 Automated chemistry modules
- Eckert and Ziegler Modular Lab Automated chemistry module
- 2 Advion Nanotek microfluidic chemistry systems
- ThalesNano H-Cube flow hydrogenation system
- Biotage microwave reactor
- Biotage Isolera 1 flash chromatography system
- Column-switching HPLC radiometabolite analysis system
- Solvent purification system
- Developmental High-Radioactivity radiochemistry area with Hot Cells
- Developmental Low-Radioactivity radiochemistry areas
- Analytical Chemistry equipment including: HPLC, GC, LC/MS, LC/MS/MS, NMR and TLC
- High-Purity Germanium Radiation Detector
- Ga68/Ge68 generator
- 2 Shielded fume hoods
- 12 fume hoods
- Shielded Iodination hood
- Perkin Elmer Wallac 2480 gamma counter
Inquiries for PET radiotracer production for radiochemistry, preclinical or clinical studies should be directed to Dr. Neil Vasdev.