Institutul National de Cercetare-Dezvoltare

IFIN-HH pentru Fizica si Inginerie Nucleara

“Horia Hulubei”

Departamentul Radiofarmaceutice, Compusi Marcati si Surse Industriale

Str. Atomistilor 407, Com.Magurele, jud.Ilfov, C.P. MG-6, cod 077125
tel. (021) 404.23.00; fax (021) 457.44.40; (021) 457.44.32

Manual de prezentare

CANTER-Redifos
Radioterapia cancerului osos
si a metastazelor osoase generalizate

Palliative analgesic therapy of generalised

metastatic process in skeletal tissue
Institutul National de Cercetare-Dezvoltare pentru
Fizica si Inginerie Nucleara “Horia Hulubei”

Departamentul Radiofarmaceutice, Compusi

Marcati si Surse Industriale

Dr. Dana Niculae Dr. Valeria Lungu

Dr. Diana Chiper

Manual de prezentare
CANTER-Redifos

Radioterapia cancerului osos

si a metastazelor osoase generalizate
Palliative analgesic therapy of generalised
metastatic process in skeletal tissue

Finantat prin
Programul National de Cercetare-Dezvoltare si Inovare
“Viata si Sanatatea”
PNCDI VIASAN
(Contract 284 / 2003)

ISBN 973-0-03802-3
 Tiparit: Martie 2005
IFIN-HH
Nr exemplare: 100
ISBN 973-0-03802-3

Responsabil produs
Dr. Dana Niculae
Institutul de Fizica si Inginerie Nucleara “Horia Hulubei”
Departamentul Compusi Marcati si Radiofarmaceutice (CPR)
Str. Atomistilor nr. 407 Magurele, jud Ilfov
Tel. +4 021 4042300 int 4518
Fax +4 021 4574440
E-mail radphy@ifin.nipne.ro
Cuprins / Content

 Introducere / Introduction 5
 Metastaze osoase / Bone metastases 6
 Imagistica si terapia cancerului si metastazelor
osoase / Bone imaging and therapy 8
 Re-188 / Re-188 11
 188Re(Sn)HEDP / 188Re(Sn)HEDP 12
CANTER-Redifos
 Caracteristicile procesului de marcare / Labelling
process parameters 13
 Schema de preparare / Preparation procedure 14
 Stabilitatea in vitro / In vitro stability 15
 Controlul de calitate / Quality control 16
 Biodistributia / Biodistribution 17
 Recomandari / Recommendations 18
 Bibliografie / References 19
 Introducere
Metastazele osoase apar frecvent, la peste 70% din
pacientii suferind de cancer de san sau prostata in faze
avansate [1], si la aproximativ 15 – 30 % din cazurile
diagnosticate cu carcinom pulmonar, al colonului, stomacului,
vezicii urinare, uterului, rectului, tiroidei sau renal.
Consecintele metastazelor osoase sunt adesea
devastatoare. Astfel, metastazele osteolitice pot cauza dureri severe,
fracturi patologice, hipercalcemie cronica, compresie spinala sau alt
sindrom de compresie a sistemului nervos. Metastazele osteoblastice
induc, de asemenea, dureri osoase si fracturi patologice cauzate de
calitatea slaba a tesutului osos produs de osteoblaste [2]. Mai mult,
cancerul este in general incurabil atunci cand tumora primara
metastazeaza in os: numai 20 de procente din pacientele cu cancer
de san supravietuiesc 5 ani de la descoperirea metastazelor osoase
[3].

Introduction
Bone metastases are frequent complication of cancer
occurring up to 70 percent of patients with advanced breast or
prostate cancer [1] and in approximatively 15 to 30 percent of
patients with carcinoma of the lung, colon, stomach, bladder, uterus,
rectum, thyroid or kidney.
The consequences of bone metastasis are often devastating.
Osteolytic metastases can cause severe pain, pathologic fracture,
life-threatening hypercalcemia, spinal cord compression and other
nerve-compression syndromes. Patients with osteoblastic
metastases have bone pain and pathologic fractures because of
poor quality of bone produced by the osteoblasts [2]. Furthermore
once tumors metastasize to bone they are usually incurable: only 20
percent of patients with breast cancer are still alive five years after
the discovery of bone metastases [3].
Metastaze Bone
osoase Metastases

Fig 1 Procesul de remodelare osoasa prin osteoblaste si osteoclaste /

Bone remodeling process through osteoblasts and osteoclasts
Metastases have been
Metastazele au fost characterized as osteolytic or
caracterizate ca fiind osteolitice osteoblastic. This classification
sau osteoblastice. Aceasta actually represents two extremes
clasificare reprezinta de fapt of a continuum in which
extremele situatiilor reale in care dysregulation of the normal bone
intervine o alterare a procesului de remodeling process occurs (Figure
remodelare osoasa (Figura 1). 1). Patients can have both
Pacientii pot prezenta atat osteolytic and osteoblastic
metastaze osteolitice sau metastasis or mixed lesions
osteoblastice cat si leziuni mixte containing both elements [2].
continand ambele elemente [2].
Several factors account for
Mai multi factori sunt the frequency of bone metastasis.
raspunzatori pentru frecventa Blood flow is high in areas of red
ridicata a metastazelor osoase. marrow [4], accounting for the
Fluxul sanguin crescut prezent la predilection of metastases for
nivelul maduvei rosii [4] este those sites. Furthermore, tumor
raspunzator pentru predilectia cells produce adhesive molecules
localizarii metastazelor in aceste that bind them to marrow stormal
zone. cells and bone matrix.
 Metastaze osoase / Bone metastases

In plus, celulele tumorale produc molecule adezive prin care se

leaga atat la celulele stormale ale maduvei osoase, cat si la
matricea osoasa.
Tesutul osos depoziteaza, de asemenea, factori de
crestere imobilizati, proteine morfogenetice si calciu [5]. Remo-
delarea sistemului osos
adult, se realizeaza
continuu, prin activitatea
coordonata a osteoclastelor si
osteoblastelor la suprafata
trabeculara si sistemului
harvesian. In tesutul normal
acest proces de remodelare se
desfasoara dupa secventa:
osteoclastele resorb tesutul
urmand ca osteoclastele sa-l
reformeze, in aceeasi zona
(Figura 2).

Fig 2
Procesele de resorbtie (A)
si formare (B) a tesutului osos
Bone resorption (A)
and bone formation (B) processes

Bone is also a large repository

for immobilized growth factors,
bone morphogenetic proteins
and calcium [5]. The adult
skeleton continually turns over
and remodels itself through the
coordinated activity of
osteoclasts and osteoblasts on
trabecular surfaces and the
harvesian system. In normal
bone there is a balanced
remodeling sequence: first
osteoclasts resorb bone, and
than osteoblasts form bone at
the same site (Figure 2).
 Imagistica si terapia
cancerului si metastazelor
osoase
Ionii anorganici au fost primii compusi utilizati in
imagistica sistemului osos datorita binecunoscutului proces
de schimb ionic ce se petrece la nivelul osului. Utilizarea fluorului
este limitata de energia sa înalta iar a strontiului de captarea lenta
si dezintegrarea rapida.
Primii agenti ai Tc-99m utilizati in scintigrafia osoasa au fost
polifosfatii. Susceptibiliatea ca legatura P-O-P sa fie atacata de
enzimele fosfataze, a condus la dezvoltarea fosfonatilor continand o
legatura P-C-P, cel mai performant reprezentant al acestei clase
fiind MDP (acidul metilendifosfonic). Mecanismul captarii
difosfonaţilor, in special a MDP, cu o structura posibila de tipul:
[Tc(MDP)(OH)]n- se bazeaza pe potrivirea spatiilor dintre atomii O-
donori din MDP cu spatiile dintre ionii de Ca din cristalele de
hidroxiapatita (3,44 A) cu structura de tipul:
[3Ca3(PO4)2Ca(OH)2]
Studiile autoradiografice au aratat ca legarea fosfonatilor la
suprafata cristalului osos pare a fi ireversibila, compusul fiind
incorporat in structura cristalului.

Bone metastases
imaging and therapy
Inorganic ions were the first materials to be used in bone
imaging because of the known mineral exchange processes in bone.
Fluorine use is limited by high energy, strontium by slow uptake and
rapid decay.
The first technetium agents used were the polyphosphates,
but these proved less than ideal because of the susceptibility of the P-
O-P link to attack by phosphatase enzymes. Development of the
phosphonates containing a P-C-P link resolved this problem. The most
important compound of this class is MDP (methylenediphosphonic
acid). Mechanism of uptake of diphosphonates, especially MDP with a
possible structure [Tc(MDP)(OH)]n-, is based on spacing of O- donor
Imagistica si terapia cancerului si metastazelor
osoase / Bone metastases imaging and therapy
atoms in MDP matches the spacing of the Ca ions on
hydroxyapatite crystals (3.44 A) with following structure:
[3Ca3(PO4)2Ca(OH)2]
Early autoradiographic studies showed that the
binding of phosphates to the bone crystal surface appeared to be
irreversible, with the compounds becoming incorporated into the
crystal structure.
Phosphonates can form monomeric and polymeric species
around the Me(IV) core, up to 11 molecular species with different
molecular weights have been identified by HPLC. Complexes formed
around Me(V)core (MW 820 – 880 d) shows best ratio between bone
uptake and urine clearance.
The prelevance of metastatic bone disease in all countries,
both developed and developing, creates a large demand for new
therapeutic and palliative agents. A great interest for radiotherapy of
skeletal metastases is represented by phosphonic acid chelates labeled
with β-emitting therapeutic radionuclides such as 186,188Re, 153Sm, 177Lu,
166Ho [6,7]. Radiolabeling of a wide range of phosphonates ligands,

such as: HEDP, DOTMP, EDTMP, TTHMP with beta-emitters lead to

complexes with synergic biological activity at manifest lesions due to
both beta-radiolysis and chemotherapeutic effect of ligands [7-9].
These studies highlight the interdependency between

chemical structure of the ligand and biologic

behavior (biodistribution) of the labelled phosphonates.

MDP (methylene diphosphonic acid / acid metilen difosfonic)

HEDP (1hydroxyethylidene diphosphonic acid / acid 1hidroxietiliden
difosfonic )
DOTMP (tetraazacyclododecane tetramethylene phosphonic acid /
acid tetraazaciclododecan tetrametilen fosfonic)
EDTMP (ethylidene tetramethylene phosphonic acid / acid etiliden
tetrametilen fosfonic)
TTHMP (triethylenetetramine hexamethylene phosphonic acid / acid
trietilentetramino hexametilen fosfonic)
Imagistica si terapia cancerului si metastazelor
osoase / Bone metastases imaging and therapy

Fosfonatii pot fi structurati in jurul metalului central

Me(IV), formand specii monomerice sau polimerice - au fost
identificate prin HPLC pana la 11 specii cu mase moleculare
diferite – sau in jurul Me(V) caz in care se obtin specii (MW
820 – 880 d) pentru care raportul dintre captarea la nivelul
osului si clearance-ul in urina este optim.
Frecventa metastazelor osoase, atat in tarile dezvoltate cat
si in cele in curs de dezvoltare, a dus la experimentarea si testarea de
noi agenti terapeutici si paleativi. De mare interes in radioterapia
metastazelor osoase sunt chelatii acizilor fosfonici radiomarcati cu β-
emitatori terapeutici, precum 186,188Re, 153Sm, 177Lu, 166Ho [6,7].
Caracteristicile fizice a acestor radonuclizi sunt prezentate in tabelul de
mai jos. Radiomarcarea unei game variate de liganzi fosfonici, printre
care: HEDP, DOTMP, EDTMP, TTHMP cu unul din beta emitatorii
enumerati conduce la formarea unor complecsi cu activitate biologica
sinergica la nivelul leziunilor, datorata atat efectelor radiolitice cat si
efectului chimioterapeutic al ligandului [7,9]. Aceste studii au evidentiat
relatia dintre:
structura chimica a ligandului si
comportamentul biologic (biodistributie)
Caracteristicile fizice ale unor β, -emitatori cu potential imagistic / terapeutic
Physical properties of some β, -emitters with imaging / therapeutic potential
Radionuclid / Energie / Energy
T½
99mTc /6,03 h (E ) 140keV – imagistica / imaging
153Sm / 47 h (Emax) 0,670 MeV (78%), 0,8 MeV (21%), (E)103 keV -
terapie (monitorare) / therapy (follow up)
177Lu / 6,7 d (Emax) 0,498 MeV (78,6%), 0,384 MeV (9,1%) 176 MeV
(12,2%), (E) 0,208 MeV (11%), 113 MeV (6,4%) - terapie
(monitorare) / therapy (follow up)
188Re / 17 h (Emax) 2,120 MeV (72%), 1,96 MeV (25%); (E)155 keV
(10%) - terapie (monitorare) / therapy (follow up)
186Re / 90 h (Emax) 0,934MeV (23,1%); 1,07MeV (73%), (E)
0,123MeV; 0,137MeV; 0,631MeV; 0,768MeV
- terapie (monitorare) / therapy (follow up)
 Re-188 / Re-188

Proprietatile chimice ale reniului sunt asemanatoare cu

cele ale technetiului. Pe aceasta baza, radiofarmaceuticele
destinate marcarii cu 99mTc, in scop imagistic, au fost marcate
cu Re si testate ca agenti terapeutici [10-12].
Caracteristicile sale nucleare
sunt: emisia beta cu energia maxima
de 2,12 MeV, capacitatea de
penetrare medie in tesuturile moi, de
3 mm, suficienta pentru terapie, si
emisia gamma (10%) insotitoare, cu
energia de 155 keV, utila pentru
monitorarea terapiei si studii de
biodistributie in vivo. 188Re are un
timp de injumatatire relativ scurt (17
ore) si poate fi produs atat prin
iradiere in reactorul nuclear cat si
prin eluarea unui generator de
188W/188Re [13,14] (Figura 3).

The chemical properties of

rhenium are similar to technetium.
Hence, rhenium analogues of
technetium radiopharmaceuticals
have been prepared and explored as
therapeutic agents [10-12]. Its
favorable nuclear parameters, i.e.
beta emissions with a maximum
energy of 2.12 MeV and an average
penetration in soft tissue of 3 mm
that are sufficient for therapy, and
also a 10% abundant, 155 keV
gamma emission make it suitable for
nuclear medicine imaging and in
vivo biodistribution studies. It has a Fig. 3. Generator de 188W/188Re
188W/188Re generator
relatively short physical half-life of
only 17 hr and can be produced
either by neutron irradiation in a
nuclear reactor or by an on-site
188W/188Re generator [13-14] (Figure
3).
188Re(Sn)HEDP 188Re(Sn)HEDP
CANTER-Redifos
Reniu-188-hidroxietiliden
difosfonatul (188Re-HEDP) este
un nou radiofarmaceutic, cu
localizare preferentiala la nivelul
metastazelor osoase, depozitand
local o radiatie beta eficienta
terapeutic.
Pentru obtinerea acestui
produs, HEDP (99,9%), un
derivat fosfonic cu activitate
biologica, a fost radiomarcat cu
radionuclidul 188Re, beta-
emitator. Pentru marcare se
utilizeaza solutie de perrenat de
sodiu, eluata de la un generator
188W/188Re si perrenat de potasiu
(solutie) ca purtator.
Fig 4 Structura HEDP in jurul metalului central /
The structure of HEDP around the core metal
Rhenium-188-hydroxy-
ethylidene diphosphonate (188Re-
HEDP) is a novel and attractive
radiopharmaceutical that localizes
in areas of osseous metastases
and emits beta particles with
energy sufficient to be
therapeutically useful.
To get the product, HEDP
(99,9%), a phosphonate with
biological activity and therapeutic
potential, was radiolabelled with the
radionuclide 188Re, a beta-emitter.
Sodium perrhenate solution, eluted
from a 188W/188Re generator was
used and potassium perrhenate
solution was added as carrier.
Caracteristicile procesului de
marcare / Labelling process
parameters
100

Reducerea Re(VII) in 90
randament
reducere /
trepte de valenta inferioare, 80
reducing yield
necesare procesului de 70 (%)

complexare cu HEDP, se face 60

90 C
25 C
cu ajutorul ionilor stanosi 50

(Sn++). 40

Procesul de marcare al 30

HEDP cu Re este caracterizat 20

de: raportul molar dintre 10

metal si agentul reducator,

0
0.4 0.8 2 4

pH, temperatura si mediul de [Sn(II)/Re(VII)]

reactie. Parametri optimi Fig. 5. Dependenta randamentului de reducere a

sunt: [Re(VII)/Sn++]=2;
90°C; pH 1,5-1,7; atmosfera
inerta (azot gaz).
Re(VII) fata de cantitatea de ioni stanosi si
temperatura de reactie/ Reduction yield of Re(VII)
as function of the stannous ions amount and
reaction temperature

The reduction of
100
Randament reducere / reduction yield (%)

Re(VII) to lower oxidation

90

30 min
state, asked by chelating
80
24 h

process, was made by

70

stannous ions (Sn++)

60

The HEDP labelling

50

process is controlled by: 40

molar ratio between ligand 30

and reducing agent, pH, 20

temperature and reaction 10

medium. The optimal 0

0.5 1 1.5 2

parameters are: [Re(VII)/ pH

Sn++]=2; 90°C; pH 1.5-1.7; Fig. 6. Randamentul de obtinere al Re-HEDP in

inert atmosphere (nitrogen functie de pH-ul de marcare / Re-HEDP yield as
gas). function of the labelling pH
Schema de preparare /
Preparation procedure

Compozitie / Formulation
15 mg HEDP;
4,5 mg SnCl2x2H20; GENERATOR
4 mg ascorbic acid; 188W/188Re
8,4 mg NaHCO3;
2,7 mg NaCl; 10 µL HCl 37%
apa pana la / water up to 1 mL 2 mL Na188ReO4
(658.6 MBq)
Sterilizare Liofilizare 150 µg KReO4
Sterilization Freeze drying

pastrare la /
Storage at
2-8°C 188Re-HEDP

pH=5,5-6

pH=1,5-1,7 NaOH 2N

baie de apa / water bath

90°C
30 min
 Stabilitatea in vitro /
In vitro Stability

100
99
98
97
RCP (%)

96
95
94
93
92
91
90
0h 4h 24h 48h

Timp (h)
.

Fig. 7. Stabilitatea 188Re-HEDP / The stability of 188Re-HEDP

Fosfonatul radiomarcat este stabil in vitro

pana la 24 ore, daca marcarea a fost relizata in conditiile
optime descrise anterior. La 48 ore post marcare PRC a
188Re-HEDP scade lent la 95% din cauza demetalizarii
complexului si reoxidarii Re la perrenat (Figura7).

The radiolabeled phosphonate are stable in

vitro up to 24h, under the optimal conditions described
earlier. At 48 h post-labeling, the RCP of 188Re-HEDP
slowly decreases to 95% due to the demetallization of
the complex and the reoxidation of Re to perrhenate as it
is shown in Figure 7.
 Controlul de calitate /
Quality control

188Re(Sn)HEDP

 PRN a eluatului de la generatorul 188W/188Re se determina prin

spectrometrie gamma de inalta rezolutie; conditia de admisibilitate:
PRN>99,5%
 PRC a eluatului de la generatorul 188W/188Re – se determina prin
cromatografie in strat subtire – TLC, solvent NaCl 0,9%; conditia de
admisibilitate: PRC>95%
 PRC a fosfonatului marcat – se determina prin TLC (placi cu silicagel
0,2mm), in solventi MEC (metil-etil cetona) si NaCl 0,9%. Conditia de
admisibilitate: PRC>95%

 RNP testing of the sodium perrhenate, eluted from 188W/188Re

generator, is performed by high resolution gamma spectrometry;
admissibility: RNP>99.5%
 RCP testing of the sodium perrhenate, eluted from 188W/188Re
generator, is performed by TLC using saline solution as the solvent;
admissibility: RNP>95%
 The RCP of the labelled phosphonate was determined by TLC, using
pre-coated plastic sheets with 0.2 mm silica gel layer, MEK and saline
as solvents; admissibility: RNP>95%

Rf-urile fosfonatului radiomarcat si ale posibilelor impuritati radiochimice /

Rf’s of the radiolabelled phosphonate and radiochemical impurities

Rf fosfonat marcat/ Rf Rf 188ReO2

labelled 188ReO4- 188Re liber / free

phosphonate
MEC / MEK 0.00 1.00 -

NaCl 0,9% 0.90-1.00 0.68-0.72 0.00-0.10

Biodistributia / Biodistribution

Dupa administrarea iv a 188Re-HEDP, se observa o

captare osoasa ridicata, rapida si stabila (Figura 8). Captarea osoasa
creste de la 71.3% la 4 h pi pana la 88.08% la 48 h pi; se observa, de
asemenea un clearance sanguin rapid, fiind evidentiata calea de
excretie renala. Testele de biodistributie au fost efectuate pe modele
animale.
After iv administration of 188Re-HEDP, rapid and stable
bone uptake was observed (Figure 8). The bone uptake was
increasing from 71.3% at 4 h pi to 88.08% at 48 h pi; fast blood-
clearance and renal excretion was also observed. Biodistribution
profile was tested on animal models.
Doza inj/g
organ(%)
Inj dose/g
organ(%)
90

80 4
24
70
48
60

50

40

30

20

10

0
48
Liver
Thyroid Blood 24 timp /
Bone time (h)
Organ Muscle
Lung
Kidney
4

GIT
Ficat Tiroida Sange Os Muschi Pulmon Rinichi GIT

Fig. 8. Biodistributia 188Re-HEDP /

The biodistribution profile of 188Re-HEDP
 Recomandari /
Recommendations

 Testele preclinice efectuate

recomanda 188Re-HEDP in
tratamentul metastazelor osoase a
carui administrare iv conduce la o
captare osoasa ridicata si stabila
(pana la 88% din doza injectata/g
organ)
 Doza terapeutica recomandata in
literatura, in urma studiilor clinice este
de 0,5 -1 mCi/kg corp [15].
 Raspunsul la tratament apare in
primele 5 zile [5].
 Durata raspunsului la tratament este
variabila, fiind cuprinsa intre 15 zile si
6 luni [5].

 Preclinical studies recommend the

use of 188Re-HEDP in treatment of
osseous metastases; its iv
administration leads to a good and
stable bone uptake (up to 88%
injected dose / g organ)
 The clinical trials conclude that the
therapeutically dose is 0,5 -1 mCi/kg
body (from literature) [15]
 Response signs to treatment
appeared within the first five days pi,
showing a remarkable recovery from
pain symptoms [5].
 Duration of reponse – variable,
between 15 days to 6 months [5].
 Bibliografie References

1. Coleman, RE, Rubens, RD The clinical course of bone metastases from

breast cancer Br J Cancer 1987; 55: 61-6
2. Rodman, GD Mechanisms of bone metastasis N Engl J Med 2004; 350 1655-64
3. Coleman, RE Metastatic bone disease: clinical features, patophysiology and
treatment strategies Cancer Treat Rev 2001; 27 165-76
4. Callahan, AP, Rice, DE, Knapp, Jr FF Rhenium-188 for Therapeutic
Applications from an Alumina-based Tungsten-188/Rhenium-188
Radionuclide Generator Nuc Compact 1989; 20: 3-6.
5. IAEA-TECDOC-1114 Synthesis and radiolabelling with 153Sm and 186Re of
bone seeking agents as therapeutic radiopharmaceuticals
6. Bouziotis, P, Pirmettis, I, Papadoupoulos, M, Varvarigou, A, Chiotellis, E A new
153Sm bone seeking agent for potential use in pain palliation J. Labelled Cpd
Radiopharm 2001; 44:S78-S80.
7. Maxon, HR, Deutsch, EA, Thomas, SR, Libson, K, Lukes, SJ, Williams, CC, Ali, S
Re-186(Sn)HEDP for treatment of multiple metastatic foci in bone: Human
biodistribution and dosimetric studies Radiology 1988; 166: 501-507.
8. Maxon, HR III, Schroder, LE, Washburn, LC, Thomas, SR, Samaratunga, RC,
Biniakiewicz, D, Moulton, JS, Cummings, D, Ehrhardt, GJ, Morris, V Rhenium-
188(Sn)HEDP for treatment of osseous metastases J Nucl Med 1998; 39: 659-
663.
9. Verdera, ES, Gaudiano, J, Leon, A, Martinez, G, Robles, V, Savio, E, Leon, E,
McPherson, DW, Knapp (Russ), Jr FF Rhenium-188-HEDP-kit Formulation and
Quality Control Radiochim Acta 1997; 79: 113-117.
10. Davis, LP, Porter, AT Systemic Radionuclide Therapy. Nuclear Medicine`s Role
in the Palliation of Painful Bone Metastases Nuc Med Annual (Edited by
Freeman LM) Raven Press New York 1995; 169-185.
11. Hashimoto, K Synthesis of a 188Re-HEDP Complex using Carrier-free 188Re
and a Study of its Stability Appl Radiat Isot 1998; 49(4): 351-356.
12. Kamioki, H, Mirzadeh, S, Lambrecht, RM, Knapp, Jr FF, Dadachova K
188W/188Re Generator for Biomedical Applications. Radiochimica Acta 1994;
65: 39-46.
13. Niculae, D, Lungu, V, Mihailescu, G, Podina, C, Purice, M 188Re(Sn)HEDP - a
therapeutic radiopharmaceutical: Preparation and biodistribution studies
Rom J Endocrinol 2001; 39: 22-27.
14. Volkert, WA, Simon, J, Ketring, AR, Holmes, RA, Lattimer, LC, Corwing, LA
Radiolabeled Phosphonic Acid Chelates: Potential Therapeutic Agents for
Treatment of Skeletal Metastates Drugs of the Future 1989; 8(14): 799-811.
15. Liepe, K, Kropp, J, Runge, R, Kotzerke, J Therapeutic Efficiency of Rhenium-
188-HEDP in human prostate cancer skeletal metastases Br J Cancer 2003;
89(4): 625-629.
 Institutul National de Cercetare-Dezvoltare
pentru Fizica si Inginerie Nucleara
“Horia Hulubei”

Departamentul Radiofarmaceutice, Compusi Marcati si

Surse Industriale

Truse pentru marcare cu Tc-99m liofilizat injectabil,

steril si apirogen, 6 flacoane multidoza/trusa

 SCINTIFIN-PIROFOSFAT
 SCINTIFIN-DTPA
 SCINTIFIN-MEDRONAT
 SCINTIFIN-GLUCOHEPTONAT
 SCINTIFIN-FITAT

Generatorul de 99Mo/99mTc
fabricat cu 99Mo de fisiune
(import MDS Nordion)
Disponibil cu activitati de
4 GBq; 8 GBq; 15 GBq; 18 GBq
Se livreaza impreuna cu trusa de
elutie (10 flacoane vidate si 5
flacoane continand NaCl 0,9%)

Generator de Tc-99m ROMTEC