Institutul National de Cercetare-Dezvoltare pentru Fizica si Inginerie Nucleara

1
Institutul National de Cercetare-Dezvoltare p
entru Fizica si Inginerie Nucleara Horia
Hulubei Departamentul
Radiofarmaceutice, Compusi Marcati si Surse
Industriale

• Manual de prezentare
• CANTER-Redifos
• Radioterapia cancerului osos
• si a metastazelor osoase generalizate

• Palliative analgesic therapy of generalised
  metastatic process in skeletal tissue

2
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)

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. [phone] int
4518 Fax [phone] E-mail radphy_at_ifin.nipne.r
o
4
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

5
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.
6
Metastazeosoase
BoneMetastases
Fig 1 Procesul de remodelare osoasa prin
osteoblaste si osteoclaste / Bone remodeling
process through osteoblasts and osteoclasts

• Metastases have been characterized as
  osteolytic or osteoblastic. This classification
  actually represents two extremes of a continuum
  in which dysregulation of the normal bone
  remodeling process occurs (Figure 1). Patients
  can have both osteolytic and osteoblastic
  metastasis or mixed lesions containing both
  elements 2.
• Several factors account for the frequency of
  bone metastasis. Blood flow is high in areas of
  red marrow 4, accounting for the predilection
  of metastases for those sites. Furthermore, tumor
  cells produce adhesive molecules that bind them
  to marrow stormal cells and bone matrix.

• Metastazele au fost caracterizate ca fiind
  osteolitice sau osteoblastice. Aceasta
  clasificare reprezinta de fapt extremele
  situatiilor reale in care intervine o alterare a
  procesului de remodelare osoasa (Figura 1).
  Pacientii pot prezenta atat metastaze osteolitice
  sau osteoblastice cat si leziuni mixte continand
  ambele elemente 2.
• Mai multi factori sunt raspunzatori pentru
  frecventa ridicata a metastazelor osoase. Fluxul
  sanguin crescut prezent la nivelul maduvei rosii
  4 este raspunzator pentru predilectia
  localizarii metastazelor in aceste zone.

7
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).

8
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 difosfonatilor, 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
9
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 ß-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)
10
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 ß-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) Caract
eristicile fizice ale unor ß, ?-emitatori cu
potential imagistic / terapeutic Physical
properties of some ß, ?-emitters with imaging /
therapeutic potential

Radionuclid / T ½ Energie / Energy
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)
11
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 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).

Fig. 3. Generator de 188W/188Re 188W/188Re
generator
12
188Re(Sn)HEDP 188Re(Sn)HEDPCANTER-Redifos

• 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.

• 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
13
Caracteristicile procesului de marcare /
Labelling process parameters
Reducerea Re(VII) in trepte de valenta
inferioare, necesare procesului de complexare cu
HEDP, se face cu ajutorul ionilor stanosi (Sn).
Procesul de marcare al HEDP cu Re este
caracterizat de raportul molar dintre metal si
agentul reducator, pH, temperatura si mediul de
reactie. Parametri optimi sunt Re(VII)/Sn2
90C pH 1,5-1,7 atmosfera inerta (azot gaz).
The reduction of Re(VII) to lower oxidation
state, asked by chelating process, was made by
stannous ions (Sn) The HEDP labelling
process is controlled by molar ratio between
ligand and reducing agent, pH, temperature and
reaction medium. The optimal parameters are
Re(VII)/ Sn2 90C pH 1.5-1.7 inert
atmosphere (nitrogen gas).
Fig. 5. Dependenta randamentului de reducere a
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
Fig. 6. Randamentul de obtinere al Re-HEDP in
functie de pH-ul de marcare / Re-HEDP yield as
function of the labelling pH
14
Schema de preparare / Preparation procedure

• Sterilizare Liofilizare
• Sterilization Freeze drying
• pH1,5-1,7

Compozitie / Formulation 15 mg HEDP 4,5 mg
SnCl2x2H20 4 mg ascorbic acid 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) 150 µg KReO4
GENERATOR 188W/188Re
pastrare la / Storage at 2-8C
188Re-HEDP pH5,5-6
NaOH 2N

• baie de apa / water bath
• 90C
• 30 min

15
Stabilitatea in vitro / In vitro Stability
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.
16
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 PRNgt99,5
• PRC a eluatului de la generatorul 188W/188Re se
  determina prin cromatografie in strat subtire
  TLC, solvent NaCl 0,9 conditia de
  admisibilitate PRCgt95
• 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 PRCgt95
• RNP testing of the sodium perrhenate, eluted from
  188W/188Re generator, is performed by high
  resolution gamma spectrometry admissibility
  RNPgt99.5
• RCP testing of the sodium perrhenate, eluted from
  188W/188Re generator, is performed by TLC using
  saline solution as the solvent admissibility
  RNPgt95
• 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 RNPgt95
• Rf-urile fosfonatului radiomarcat si ale
  posibilelor impuritati radiochimice /
  Rfs of the radiolabelled phosphonate and
  radiochemical impurities

Rf fosfonat marcat/ labelled phosphonate Rf 188ReO4- Rf 188ReO2 188Re liber / free
MEC / MEK 0.00 1.00 -
NaCl 0,9 0.90-1.00 0.68-0.72 0.00-0.10
17
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.
Organ
Fig. 8. Biodistributia 188Re-HEDP / The
biodistribution profile of 188Re-HEDP
18
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.

19
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
   44S78-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 Medicines 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.

20
Institutul National de Cercetare-Dezvoltarepentr
u Fizica si Inginerie Nucleara Horia
HulubeiDepartamentul 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