Institutul National de Cercetare-DezvoltareInstitutul National de Cercetare-Dezvoltarepentru Fizica si Inginerie Nucleara pentru Fizica si Inginerie Nucleara

“Horia Hulubei”“Horia Hulubei”

Departamentul Radiofarmaceutice, Compusi Marcati si Surse IndustrialeDepartamentul Radiofarmaceutice, Compusi Marcati si Surse Industriale

Manual de prezentareManual de prezentare

CANTER-RedifosCANTER-RedifosRadioterapia cancerului ososRadioterapia cancerului osossi a metastazelor osoase generalizatesi a metastazelor osoase generalizate

Palliative analgesic therapy of generalised metastatic process in skeletal tissue

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

IFIN-HH

Dr. Dana Niculae Dr. Valeria LunguDr. Diana Chiper

Manual de prezentare

CANTER-Redifos

Radioterapia cancerului osossi 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

Institutul National de Cercetare-Dezvoltare pentru

Fizica si Inginerie Nucleara “Horia Hulubei”

Departamentul Radiofarmaceutice, Compusi Marcati si Surse Industriale

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

Tiparit: Martie 2005IFIN-HH

Nr exemplare: 100ISBN 973-0-03802-3

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

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].

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].

Metastazeosoase

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.

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.

BoneMetastases

Fig 1 Procesul de remodelare osoasa prin osteoblaste si osteoclaste / Bone remodeling process through osteoblasts and osteoclasts

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 realizeazacontinuu, 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).

Metastaze osoase / Bone metastases

Imagistica si terapia cancerului si metastazelor

osoase

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.

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

Bone metastases imaging and therapy

Ionii anorganici au fost primii compusi utilizati in imagistica sistemului osos datorita binecunoscutului proces

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

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.

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 / terapeuticPhysical properties of some β, -emitters with imaging / therapeutic potential

Imagistica si terapia cancerului si metastazelor osoase / Bone metastases imaging and therapy

Radionuclid / T ½

Energie / Energy

99mTc /6,03 h (E ) 140keV – imagistica / imaging

153Sm / 47 h (Emax) 0,670 MeV (78%), 0,8 MeV (21%), (E)103 keV - terapie (monitorare) / therapy (follow up)

177Lu / 6,7 d (Emax) 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)

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.

188Re / 17 h (Emax) 2,120 MeV (72%), 1,96 MeV (25%); (E)155 keV (10%) - terapie (monitorare) / therapy (follow up)

186Re / 90 h (Emax) 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

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).

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].

Fig. 3. Generator de 188W/188Re 188W/188Re

generator

188Re(Sn)HEDP 188Re(Sn)HEDPCANTER-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.

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.

Fig 4 Structura HEDP in jurul metalului central /

The structure of HEDP around the core metal

Caracteristicile procesului de marcare / Labelling process parameters

0

10

20

30

40

50

60

70

80

90

100

0.5 1 1.5 2

pH

Ran

dam

ent r

educ

ere

/ red

uctio

n yi

eld

(%)

30 min

24 h

0

10

20

30

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50

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70

80

90

100

0.4 0.8 2 4

[Sn(II)/Re(VII)]

randament reducere /

reducing yield (%)

90 C25 C

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)/Sn++]=2; 90°C; 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)/ Sn++]=2; 90°C; 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

Schema de preparare / Preparation procedure

Sterilizare Liofilizare Sterilization Freeze drying

pH=1,5-1,7

Compozitie / Formulation15 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

pastrare la / Storage at

2-8°C

baie de apa / water bath90°C

30 min

2 mL Na188ReO4

(658.6 MBq)150 µg KReO4

188Re-HEDPpH=5,5-6

NaOH 2N

GENERATOR 188W/188Re

.

909192939495

96979899

100

0h 4h 24h 48h

Timp (h)

RC

P (%

)

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.

Stabilitatea in vitro /

In vitro Stability

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

Controlul de calitate / Quality control

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

188Re(Sn)HEDP

Rf fosfonat marcat/ labelled

phosphonate

Rf 188ReO4-

Rf 188ReO2188Re liber / free

MEC / MEK 0.00 1.00 -

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

Biodistributia / Biodistribution

LiverThyroid Blood

BoneMuscle

LungKidney

GIT

4

24

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Doza inj/g organ(%) Inj dose/g organ(%)

Ficat Tiroida Sange Os Muschi Pulmon Rinichi GIT

timp / time (h)

4

24

48

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.

Fig. 8. Biodistributia 188Re-HEDP /

The biodistribution profile of 188Re-HEDP

Organ

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; 27 165-764. 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-Dezvoltarepentru Fizica si Inginerie Nucleara

“Horia Hulubei”

Departamentul Radiofarmaceutice, Compusi Marcati si Surse Industriale

SCINTIFIN-PIROFOSFAT

SCINTIFIN-DTPA

SCINTIFIN-MEDRONAT

SCINTIFIN-GLUCOHEPTONAT

SCINTIFIN-FITAT

Truse pentru marcare cu Tc-99m liofilizat injectabil, steril si apirogen, 6 flacoane

multidoza/trusa

Generator de Tc-99m ROMTEC

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%)