Medicinal Chemistry: Technetium and Nuclear Medicine ICIS - CNR - Padova, Italy.

Medicinal Chemistry:Medicinal Chemistry:Technetium and Nuclear MedicineTechnetium and Nuclear Medicine

ICIS - CNR - Padova, Italy

Diagnostic Radiopharmaceuticals Market: Market Share by Modality (U.S.), 1997 - 1DiagnosticDiagnostic Radiopharmaceuticals Market: Radiopharmaceuticals Market: Market Share by Market Share by ModalityModality (U.S.), (U.S.), 1997 1997 -- 11

Imaging Modality Market Share (%)

X-ray 35Ultrasound 24Computed Tomography 20Nuclear Medicine 13Magnetic Resonance 8TOTAL 100

Source: Frost & Sullivan for J.Nucl.Med., 1998

Diagnostic Radiopharmaceuticals Market: Some Data (U.S.), 1997 - 2

DiagnosticDiagnostic Radiopharmaceuticals Market: Radiopharmaceuticals Market: Some Data (U.S.), 1997 Some Data (U.S.), 1997 -- 22

• $1 billion market (comparable to cisplatin market)

• > 80% of diagnostic scans are performed with Tc-99m

• applications (scintigraphy) in:- cardiology (50%)- oncology (30%)- neurology (10%)- other (10%)

Group 7 metals relevant to Group 7 metals relevant to Nuclear Medicine - 1Nuclear Medicine - 1

4 5 76 8 9 10 11

transition metals

TcTc

ReRe

Mn Fe

W Ir

Rh

Co

Os

Ru

Ni

Pd

PtTa

Cr

Au

Ag

Cu

Nb

V

Mo

Hf

Zr

Ti1st row

2nd row

3rd row

Tc and Re chemical propertiesTc Tc andand Re Re chemicalchemical propertiesproperties

chemical similaritieschemical similarities::

synthesissynthesisstructurestructure

chemical differenceschemical differences::

redred--ox potentialsox potentialskineticskinetics

Versatile Versatile chemistrychemistry::

- - several several oxidation statesoxidation states accessible accessible ((from from -I -I to to VII)VII)- - different different coordination numberscoordination numbers ((from from 4 4 to to 8)8)- - variousvarious donor setdonor set availableavailable

Frequency of occurrence of donor atoms vsoxidation state of structurally characterized

Tc-complexes

FrequencyFrequency of of occurrenceoccurrence of donor of donor atomsatoms vsvsoxidationoxidation state of state of structurallystructurally characterizedcharacterized

TcTc--complexescomplexes

I

II

III

IVV

VI

C

N

PAs

OS

SeCl

Br

150

F. Tisato et al.,J. Coord. Chem., 2001, 214, 43-90

Group 7 metals relevant to Group 7 metals relevant to Nuclear Medicine - 2Nuclear Medicine - 2

• radiodiagnosis

99mTc t1/2 = 6.0 h

E = 142 keV

• inorganic chemistry

99Tc t1/2 = 2.12x105 y

E = 292 keV

• inorganic chemistry

’cold’ 185/187Re

• radiometabolic theraphy

188Re t1/2 = 16.9 h

E = 2.0 MeV

186Re t1/2 = 90.0 h

E = 1.1 MeV

Inorganic Chemistry Inorganic Chemistry vsvs Nuclear Medicine Nuclear Medicine

• inorganic chemistry: 10-3 – 10-5 M (millimolar conc)

• nuclear medicine: 10-7 – 10-9 M (micro/nanomolar conc)

Conventional physico-chemical characterization

• NMR, IR, UV-vis spectroscopies• Mass spectrometry (EI, ESI)• X-ray crystal structure determination• TLC & HPLC chromatography

Radiometric characterization

• TLC & HPLC chromatography

HPLC profiles of ‘ground level’ [99Tc] and‘carrier free’ level [99mTc] preparations of

nitrido technetium heterocomplexes

HPLC HPLC profilesprofiles ofof ‘ ‘ground level’ground level’ [ [9999Tc] Tc] andand‘‘carrier free’ levelcarrier free’ level [ [99m99mTc] Tc] preparationspreparations ofof

nitrido nitrido technetium technetium heterocomplexesheterocomplexes

UV/visdetection

[99Tc]

detection

[99mTc]

The The 9999Mo/Mo/99m99mTc generatorTc generator

99Mo

99mTc

99Tc

t1/2 = 66.7 h; E- = 1.37 MeV

t1/2 = 6 h; E- = 142 KeV

Reduction of [99mTcO4]- and [188ReO4]

-ReductionReduction of [of [99m99mTcOTcO44]]-- and [and [188188ReOReO44]]

--

both isotopes are generator produced

from 99Mo or 188W, respectively

radiopharmaceutical preparation requires :

[MVIIO4]- + reducing agent + ligand [MI-V]

[MVIIO4]- + reducing-chelating agent [MI-V]

(heterofunctionalized phosphine)

Tc-99m based myocardial imaging agentscurrently utilized in the clinical practice

TcTc--99m 99m basedbased myocardialmyocardial imagingimaging agentsagentscurrentlycurrently utilizedutilized in the in the clinicalclinical practicepractice

TcTc

CNR

CNR

RNC CNR

R = CH2C(CH3)2OCH3

TcTc

O

P

CNRRNC

IV

P

P

P

Cardiolite®

OR

RR

RR R

RR

R = CH2CH2OCH2CH3

Myoview®

+ +

Radiopharmaceuticals based on the[99mTc(O)]3+ core and tetradentate ligands

RadiopharmaceuticalsRadiopharmaceuticals based on the based on the[[99m99mTc(O)]Tc(O)]3+3+ core core and tetradentate and tetradentate ligands ligands

TTc O

N

N

N

N

O OH

Tc(O)(HM-PAO)

®Ceretec

N

N

N Tc

S

O

O

COOH

O

O

[TcO(MAG3)]-

®TechneScan

STc

NN

H COOEtEtOOC

S

O

TcO(ECD)®Neurolite

[[99m99mTcN-TcN-NOEtNOEt]]

TcTc

N

S

SS

SNN

OO

• neutral myocardial perfusion agent (phase III)

Pasqualini et al., J. Nucl. Med., 1994, 35, 334

Biomolecules: the bifunctional approachBiomoleculesBiomolecules: : thethe bifunctional bifunctional approachapproach

M linker

BFCA

bio-activefragment

Biomolecules: the bifunctional approachBiomoleculesBiomolecules: : thethe bifunctional bifunctional approachapproach

M = [TcVO]3+

BFCA = N2S2 type

tropane analog

TcTc

O

SS

NNN

Cl

[99mTc]TRODAT-1

Kung, M. P.; et al. J. Med. Chem. 1997, 41, 428

The bifunctional approach in The bifunctional approach in mixed nitrido-Tc heterocomplexesmixed nitrido-Tc heterocomplexes

The bifunctional approach in The bifunctional approach in mixed nitrido-Tc heterocomplexesmixed nitrido-Tc heterocomplexes

TcTc

N

P

P

N

O

S

ON

O

S

N N

O

H

H H

MW = 913

The substitution-inert The substitution-inert [Tc(N)(PXP] synthon[Tc(N)(PXP] synthon

Tc

N

X

Cl

ClP

P

Y

Z

P

P

Tc

N

X

Bolzati et al., J. Am. Chem. Soc. 124, 2002, 11468

Crystal structure of [Re(N)(dedc)(pnp2)]+

• pseudo-octahedron

• cis-P co-ordination P(1)-Re-P(2) = 101.2(1)°

• trans-N co-ordination N(1)-Re-N(2) = 164.5(5)°

Re-N(2) = 2.73(1) Å

From aryl- to alkyl-diphosphinesFrom aryl- to alkyl-diphosphines

PN P

O

pnp2

S

S

N

dedc

S

S

N

O

O

dbodc

POO N P

O

O

O

pnp5

ESI - MS of [ESI - MS of [9999Tc(dbodc)(pnp5)]Tc(dbodc)(pnp5)]++

100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500m/z

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

Rel

ativ

e A

bund

ance

846.6

848.6

640.6527.4 849.5844.7279.4 552.8306.5 641.6371.4 862.5788.5413.5185.3 961.81049.9130.6 1139.01183.9 1401.21314.2 1454.4

M+

[Tc(N)Cl2(PPh3)2]

DCM i) pnp5 ii) dbodc

yellow oil

E. Marotta et al, RCM, 2003, submitted

[99Tc(N)(dbodc)(pnp5)]+[[9999Tc(N)(Tc(N)(dbodcdbodc)(pnp5)])(pnp5)]++

TcTc

N

P

P

N

S

SN

O

O

O

O

O

O

O +

Collisional experiments on [Collisional experiments on [9999Tc(N)Tc(N)(bdodc)(pnp5)](bdodc)(pnp5)]+ + -- MSMS22

- PO

O

- HPO

O

250 300 350 400 450 500 550 600 650 700 750 800 850 900 950 1000m/z

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

Rel

ativ

e A

bund

ance

640.3

641.3

847.4

668.2

846.4669.3

553.2569.2527.2405.1348.0 582.3608.3406.1 844.3813.3775.3297.1276.0 452.3318.0 496.1 758.2714.5 868.9

Collisional experiments on [Collisional experiments on [9999Tc(N)Tc(N)(bdodc)(pnp5)](bdodc)(pnp5)]+ + -- MSMS33

200 250 300 350 400 450 500 550 600 650 700 750 800 850 900 950 1000m/z

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

80

85

90

95

100

Rel

ativ

e A

bund

ance

594.2

403.0

640.2

568.2435.0 608.2401.1 527.0331.0 493.1 566.1284.7247.8 462.2227.2 865.4 914.8640.9

-

-

-

SHS C N

O

OH

SHS C N

O

O

Collisionally induced fragmentation Collisionally induced fragmentation pattern of [pattern of [9999Tc(N)(dbodc)(pnp5)]Tc(N)(dbodc)(pnp5)]++

TcN S

SPC N

O

O

N

O

O

O

NN Tc

O

POO

TcP S

SPC N

O

O

N

N

O

O

O

OO

S

NN Tc

SON

O

O

P

OO

C

S

NN Tc

SON

O

P

OO

CS

NN Tc

SON

O

O

P

O

C

m/z 846

m/z 668

m/z 640

m/z 403

m/z 594

or

- C2H4

O

OH

or

SHS C N

O

O

SHS C N

O

-

-

-

-

PO

O

HPO

O--

11H NMR of [H NMR of [9999Tc(N)(dbodc)(pnp5)]Tc(N)(dbodc)(pnp5)]++

(ppm)

0.60.81.01.21.41.61.82.02.22.42.62.83.03.23.43.63.84.04.24.4

(ppm)

0.60.81.01.21.41.61.82.02.22.42.62.83.03.23.43.63.84.04.24.4

(ppm)

0.60.81.01.21.41.61.82.02.22.42.62.83.03.23.43.63.84.04.24.4

S

S

N

O

O

dbodc

99Tc-complex

POO N P

O

O

O

pnp5

11H-H-11H COSY-45 of [H COSY-45 of [99g99gTc(N)(dbodc)(pnp5)]Tc(N)(dbodc)(pnp5)]++

dbodc N-CH2-CH2-O-

dbodc -O-CH2-CH3

pnp5 -O-CH2-CH3

pnp5 N-CH2-CH2-O-

3131P and P and 1313C NMR of [C NMR of [9999Tc(N)(dbodc)Tc(N)(dbodc)(pnp5)](pnp5)]++

(ppm)

152025303540455055606570

-C-CH3-O-CH3

various CH2

(ppm)

5101520253035404550556065707580859095

30.2 ppm

impurityoxidized pnp5

11H - H - 1313C HMQC of [C HMQC of [9999Tc(N)Tc(N)(dbodc)(PNP5)](dbodc)(PNP5)]++

C-CH3

C-C and P-C

O-CH3

N-C region

O-C regionP-…CH2-O-

TcTc

N

P

P

NSS N

O

O

O

OO

OO +

Nitrido-Nitrido-99m99mTc(V) hetero-complexes:Tc(V) hetero-complexes:heart uptake in ratsheart uptake in rats

%ID/g

time (min)2 30

5

10 20 12060

1

2

3

4

6

5

99mTc-MyoviewMyoview

99mTc-CardioliteCardiolite

99mTc-DBODC5DBODC5

A. Boschi et al., J. Nucl. Med. 2003, in press

Nitrido-Nitrido-99m99mTc(V) hetero-complexes:Tc(V) hetero-complexes:heart/liver ratio in ratsheart/liver ratio in rats

time (min)

99mTc-MyoviewMyoview

99mTc-CardioliteCardiolite

99mTc-DBODC5DBODC5

h/l

2 30

25

10 20 12060

5

10

15

20

30

5

35

Nitrido-99mTc(V) hetero-complexes:Nitrido-99mTc(V) hetero-complexes:micro-SPET analysismicro-SPET analysis

Nitrido-Nitrido-99m99mTc(V) hetero-complexes:Tc(V) hetero-complexes:micro-SPET analysismicro-SPET analysis

Cardiolite®by Dupont

NOEt by Cis-Schering

Tc(N)DBODC5 by Nihon Medi-Physics