triumf-mds-nordion radiopharmaceutical r&d collaboration

TRIUMF-MDS-Nordion Radiopharmaceutical R&D

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.

MDSN-TRIUMF CollaborationWhy Now

• MDSN mandate for more R&D

• Peter Covitz as Senior VP Innovation

• Dennis Wester Vancouver Ops. Director of Applied Research

• Cara Ferreira (PhD, TRIUMF/UBC) Vancouver Ops. Applied R&D

• TRIUMF’s new Nuclear Medicine Division

TRIUMF/MDS-Nordion Collaboration (NSERC-CRD)

Enabling Technologies for Metallic Radioisotopes in Nuclear Medicine

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

Medicinal InorganicChemistry Group

Chris Orvig and Michael J. AdamMedicinal Inorganic Chemistry

Group and TRIUMF

University of British ColumbiaVancouver BC, Canada

Carbohydrate Conjugates for SPECT

Medicinal Inorganic Chemistry



Increase availability of FDG-like imaging Generator produced isotopes Isotopes with longer half-lives

Develop an FDG-like radiotherapeutic -emitting isotopes

Research Goals




FDGM = 99mTc, 186Re …64Cu, 68Ga

OHO

HO18F

OH

OHM

H2O

H2O CO

CO

OH2

CO

+

- an inexpensive, more available way to use the powerful tool of glucose imaging

- a glucose analogue that can be used for radiotherapy

FDG and PET vs. -Emission and SPECT




OHO

HO

O

OH

NH2

NH2

OH

OHO

HOOH

O

OH

NH2

NH2

OHO

HOOH

OH

OOHO

OH

O

OH

NH2

NH2

OHO

HOOH

ONH2

NH2

O

HOOH

ONH2

NH2

OH

O

HO

ONH2

NH2

OH OH

OH

NH2

NH2

OHO

HOOH

OH

O

OO

HOHO

OH

OH

OH

1,3-Diamino-2-propyl- D-glucopyranoside (L2)1,3-Diamino-2-propyl- D-xylopyranoside (L1)

1,3-Diamino-2-propyl- D-mannopyranoside (L3) 1,3-Diamino-2-propyl- D-galactopyranoside (L4)

1,3-Diamino-2-propyl- D-galactopyranoside (L5) 1,3-Diamino-2-propyl--(-D-glucopyranosyl-(1-4)-D-

glucopyranoside (L6)

Bis(aminomethyl)bis[(-D-glucopyranosyloxy)methyl]methane) (L7)

Y. Mikata et al. J. Org. Chem. 2001, 66, 3783T. Storr et al. Chem. Eur. J. 2005, 11, 195

1,3-Diaminocarbohydrate Ligands




HOO

HONH2

OH

OH

Glucosamine

N N

N

O

HN

OHOHO

OH

OH

MN

N CO

CO

N

CO

sugar

+

O

M = Re, 99mTc, 186Re

- 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

Tripodal Glucosamine Conjugate




Tridentate Ligands



OHO

HONH

OH

OH

O

N

NHO

OHO

HONH

OH

OH

O

N

N N

OHO

HOOH

S

OH

N

N

N

OHO

HOOH

O

OH

N

N

N

L1 L2

L3L4

OHOHO

NHOH

OH

O

M

N O

OC CO

N

CO

Figure 2.

N

N

HO

R

donor atoms

spacer

n

conjugation handle

N. C. Lim et al. Inorg. Chem. 2008, 47, 1337


• Procedure for radiolabeling (TRIUMF)

• 99mTc (as 99mTcO4-) added to kit containing boranocarbonate

K2[H3BCO2] 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

99mTc Chemistry




the glucose analogue: T. Storr et al. Inorg. Chem. 2005, 44, 2698

Re1




• 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.

3060

120

glucosamine

glucosethioglucose

0

0.5

1

1.5

2

2.5

3

Time

Tumour to Blood Ratio

3060

120

glucosamine

glucosethioglucose

0

0.5

1

1.5

2

2.5

Time

Tumour to Muscle Ratio

Biodistribution Ratios



Co-workers: Cheri Barta (Ph.D. 2007, UGF)Meryn Bowen Chuck Ewart (M.Sc. 2006)Cara Ferreira (Ph.D. 2006, NSERC)Dr. Neil LimTim Storr (Ph.D. 2005, NSERC)

Funding: Natural Sciences and Engineering Research Council (Strategic)Canada Foundation for Innovation (C-HORSE)MDS NordionTRIUMF

Collaborators: Dr. Anna Celler, Medical Imaging Research group, VGHFabio Marques, Univ. São PauloDr. Thomas J. Ruth, TRIUMFProfs. Shigenobu Yano and Yuji Mikata, Nara Women’s UniversityDr. Don Yapp, BC Cancer Agency

Thanks




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)

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

68Ga and 111In Chemistry

• Similar Chemistry

• Largely underutilized in Radiopharmaceutical field

• 68Ga, t1/2=68 min from Ge generator

• 111In, t1/2=67h, can be used for imaging up to a week, has 171 and 245 gammas and an Auger emission for therapy.

Other Ligands

N

N N

OH

O

O OH

O

HO

N

N N

OH

HO

OH

N

N N

SH

SH

HS

N

N N

SH

HS

SH

1 2 3 4

New Ligands

HN

NH

NH

HN

NH

NH

SH

HS

SH

HS

SH

SHN

NN

N

HS

SH

SH

HS

7 8 9

Fatty Acid Complexes

(CH2)nCO2-N

NN

-O2C

Ga

2

-

12

triumf-mds-nordion radiopharmaceutical r&d collaboration

Documents

high tumour

isotopes isotopes

triumfubc vancouver

imaging generator

mdsnottawa heart collab

glucosamine complex

kit solution

neil lim