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 laboratory has several active areas of research including:
- New Approaches for Neuroimaging, particularly in Alzheimer's Disease
- Multi-Step Chemistry with Short-Lived Radionuclides - "Total Radiosynthesis"
- Flow Radiochemistry - Microfluidic Platform
- Advanced Radiochemical Reactions - 11C-Carbonylation Chemistry
- 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
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.
We are focusing on discovering new PET radiopharmaceuticals that show promise in addressing the role of alternate targets in the pathobiology of AD. Work on these projects is being conducted by Dr. Steven Liang, Dr. Benjamin Rotstein, Dr. Lee Collier, Dr. Nicky Stephenson, Dr. Timothy Shoup and Dr. Jason P. Holland.
- T. Shoup, D. Yokell, P. Rice, R.J ackson, E.Livni, K. Johnson, T. Brady and N. Vasdev. “A Concise Radiosynthesis of the Tau Radiopharmaceutical, [18F]T807”. Journal of Labelled Compounds and Radiopharmaceuticals Volume 56 (2013) 736-740.
- J. Holland, S. Liang, B. Rotstein, T. Collier, N. Stephenson, I. Greguric and N. Vasdev “Alternative approaches for PET radiotracer development in Alzheimer’s disease: Imaging beyond plaque” Journal of Labelled Compounds and Radiopharmaceuticals. (2014) In press.DOI: 10.1002/jlcr.3158.
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. Work on these projects is being conducted by Dr. Steven Liang, Dr. Benjamin Rotstein, Dr. Lee Collier and Dr. Nicky Stephenson.
- N. Vasdev, S. Natesan, L. Galineau, A. Garcia, W. T. Stableford, P. McCormick, P. Seeman, S. Houle, A. A. Wilson, Synapse, 2006, 60, 314.
- N. Vasdev, P. Dorff, A. Gibbs, E. Nandanan, L. Reid, J. O’Neil and H. VanBrocklin. Journal of Labelled Compounds and Radiopharmaceuticals, Volume 48 (2005) 109-115.
- K. Stephenson, A. Wilson, J. Meyer, S. Houle and N. Vasdev. Journal of Medicinal Chemistry, Volume 51 (2008), 5093-5100.
- N. Vasdev, J. Chio, E. van Oosten, M. Nitz, J. McLaurin, D. Vines, S. Houle, R. Reilly and A. Wilson. Chemical Communications, (2009) 5527-5529.
N. Vasdev, E. van Oosten, K. Stephenson, N. Zadikian, A. Yudin, A. Lough, S. Houle and A. Wilson. Tetrahedron Letters, Volume 50 (2009) 544-547.
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 . Work on these projects is being conducted by Dr. Steven Liang, Dr. Benjamin Rotstein and Dr. Lee Collier.
- S. Liang, T. Collier, B. Rotstein, R. Lewis, M. Steck, and N. Vasdev. “Rapid Microfluidic Flow Hydrogenation for Reduction or Deprotection of 18F-Labeled Compounds”. Chemical Communications. Volume 49, Number 78 (2013) 8755 – 8757.
- S. Liang, D. Yokell, R. Jackson, P. Rice, R. Callahan, K. Johnson, D. Alagille, G. Tamagnan, T. Collier and N. Vasdev. “Microfluidic continuous-flow radiosynthesis of [18F]FPEB suitable for human PET imaging.” Medicinal Chemistry Communications. Volume 5 (2014) 432-435.
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.
Work on 11C-carbonylation chemistry is being conducted by Dr. Steven Liang, Dr. Benjamin Rotstein, Dr. Lee Collier and Dr. Jason P. Holland.
B. Rotstein, S. Liang, J. Holland, T. Collier, J. Hooker, A. Wilson and N. Vasdev. “11CO2 Fixation: A Renaissance in PET Radiochemistry.” Chemical Communications, Volume 49 (2013) 5621-5629.
B. Rotstein, J. Hooker, J. Woo, T. Collier, T. Brady, S. Liang and N. Vasdev. "Synthesis of [11C]bexarotene by Cu-mediated [11C]carbon dioxide fixation and preliminary PET imaging." ACS Medicinal Chemistry Letters (2014) in press. doi:10.1021/ml500065q.
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.
This work is being conducted by Dr. Jason P. Holland in collaboration with the Cyclotron PET Core at Massachusetts General Hospital as well as industrial and other academic partners.
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.
- Jason P. Holland and Neil Vasdev. Dalton Transactions. (2014) In press.
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.
- J. P. Holland, P. Cumming and N. Vasdev, J. Nucl. Med., 2012, 53(9), 1333-1336.
- J. P. Holland, P. Cumming and N. Vasdev, Amer. J. Nucl. Med. Mol. Imaging, 2013, 3(3), 194-216.
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.