TRIUMF-MDS-Nordion Radiopharmaceutical R

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TRIUMF-MDS-Nordion Radiopharmaceutical RD
Collaboration

• TRIUMF and MDSN signed MOU
• Both agreed to invest 250K each into a new
  radiochem lab in the MHESA basement
• Possible matching funds from NSERC of another
  250K.
• Expected to Grow much larger and is expected to
  be modeled after MDSN-Ottawa Heart Collab.

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MDSN-TRIUMF CollaborationWhy Now

• MDSN mandate for more RD
• Peter Covitz as Senior VP Innovation
• Dennis Wester Vancouver Ops. Director of Applied
  Research
• Cara Ferreira (PhD, TRIUMF/UBC) Vancouver Ops.
  Applied RD
• TRIUMFs new Nuclear Medicine Division

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TRIUMF/MDS-Nordion Collaboration (NSERC-CRD)
Enabling Technologies for Metallic Radioisotopes
in Nuclear Medicine
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Team

• Michael Adam-PI (TRIUMF)
• Chris Orvig-Co-applicant (UBC Chem)
• Dennis Wester-Collaborator (MDSN)
• Cara Ferreira-Collaborator (MDSN)
• Eric Price (Graduate Student, May 1/09)
• Eszter Boros (PhD Student)
• Jacqueline Cawthray, PDF

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Carbohydrate Conjugates for SPECT
Chris Orvig and Michael J. Adam Medicinal
Inorganic Chemistry Group and TRIUMF University
of British Columbia Vancouver BC, Canada
Medicinal Inorganic Chemistry Group
Medicinal Inorganic Chemistry
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Research Goals

• Increase availability of FDG-like imaging
• Generator produced isotopes
• Isotopes with longer half-lives
• Develop an FDG-like radiotherapeutic
• ?-emitting isotopes

Medicinal Inorganic Chemistry Group
Medicinal Inorganic Chemistry
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FDG and PET vs. ?-Emission and SPECT
FDG
M 99mTc, 186Re 64Cu, 68Ga
- an inexpensive, more available way to use the
powerful tool of glucose imaging - a glucose
analogue that can be used for radiotherapy
Medicinal Inorganic Chemistry Group
Medicinal Inorganic Chemistry
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1,3-Diaminocarbohydrate Ligands
Y. Mikata et al. J. Org. Chem. 2001, 66, 3783 T.
Storr et al. Chem. Eur. J. 2005, 11, 195
Medicinal Inorganic Chemistry Group
Medicinal Inorganic Chemistry
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Tripodal Glucosamine Conjugate

• - increasing evidence that N-functionalized
  glucosamines show activity with GLUT and
  hexokinase
• recent work with ECDG has shown that molecule
  uses a hexosamine transporter to gain cell access
  (D. J. Yang et al. Radiology, 2003, 226, 465)
• - high yield radiolabelling
• - HPLC concordance
• stable 24 hr. vs. 1 mM His/Cys (100x xs)

T. Storr et al. Dalton Trans. 2005, 654
Medicinal Inorganic Chemistry Group
Medicinal Inorganic Chemistry
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Tridentate Ligands
N. C. Lim et al. Inorg. Chem. 2008, 47, 1337
Medicinal Inorganic Chemistry Group
Medicinal Inorganic Chemistry
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99mTc Chemistry

• Procedure for radiolabeling (TRIUMF)
• 99mTc (as 99mTcO4-) added to kit containing
  boranocarbonate K2H3BCO2 to produce the
  99mTc(H2O)3(CO)3 precursor
• Excess ligand (10-3 M) added to the kit
  solution to ensure complete complexation

R. Alberto et al. J. Am. Chem. Soc. 2001, 123,
3135
Medicinal Inorganic Chemistry Group
Medicinal Inorganic Chemistry
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the glucose analogue T. Storr et al. Inorg.
Chem. 2005, 44, 2698
Medicinal Inorganic Chemistry Group
Medicinal Inorganic Chemistry
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Biodistribution Ratios

• Tumour to blood ratio increases over time for
  the glucose and thioglucose complexes, and
  remains constant for the glucosamine complex.
• All compounds had high tumour to muscle ratios.

Medicinal Inorganic Chemistry Group
Medicinal Inorganic Chemistry
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Thanks
Co-workers Cheri Barta (Ph.D. 2007, UGF) Meryn
Bowen Chuck Ewart (M.Sc. 2006) Cara
Ferreira (Ph.D. 2006, NSERC) Dr. Neil Lim Tim
Storr (Ph.D. 2005, NSERC)
Funding Natural Sciences and Engineering
Research Council (Strategic) Canada Foundation
for Innovation (C-HORSE) MDS Nordion TRIUMF C
ollaborators Dr. Anna Celler, Medical Imaging
Research group, VGH Fabio Marques, Univ. São
Paulo Dr. Thomas J. Ruth, TRIUMF Profs.
Shigenobu Yano and Yuji Mikata, Nara Womens
University Dr. Don Yapp, BC Cancer Agency
Medicinal Inorganic Chemistry Group
Medicinal Inorganic Chemistry
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NSERC-CRD Project
Focuses on the chemistry of 68Ga and 111In
complexes

• Ga and In have similar chemistry
• The company has targeted these two radiometals as
  having significant potential while being largely
  underutilized in the radiopharmaceutical field
• Funding 600K over 3 years (NSERC-CRD)

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New Bifunctional Chelators

• Greater stability
• Milder conditions for chelations
• Better clearance properties of complexes
• Higher radiochemical yields
• Less purification
• Reduce loss of In to Transferin
• Try to make agents to compete with 99mTc

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68Ga and 111In Chemistry

• Similar Chemistry
• Largely underutilized in Radiopharmaceutical
  field
• 68Ga, t1/268 min from Ge generator
• 111In, t1/267h, can be used for imaging up to a
  week, has 171 and 245 gammas and an Auger
  emission for therapy.

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Other Ligands
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New Ligands
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Fatty Acid Complexes