Distribuição intragástrica de refeições com 60 ml e 180 ml: três segmentações proximal-distal empregando a cintilografia

Pós-graduação em Biologia Geral e Aplicada - IBB

Detecção do lindonodo sentinela com 99m Tc-Fitato em pacientes com carcinoma invasor do colo uterino

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Otimização da circulação linfática em pacientes pós-linfadenectomia radical axilar recente por meio da estimulação linfonodal avaliada pela linfocintilografia

Pós-graduação em Ginecologia, Obstetrícia e Mastologia - FMB

Desenvolvimento de um escore preditor da eficácia do tratamento quimioterápico pré-operatório em mulheres com carcinoma de mama localmente avançado

Pós-graduação em Ginecologia, Obstetrícia e Mastologia - FMB

Polymeric micelles and molecular modeling applied to the development of radiopharmaceuticals

Micelles composed of amphiphilic copolymers linked to a radioactive element are used in nuclear medicine predominantly as a diagnostic application. A relevant advantage of polymeric micelles in aqueous solution is their resulting particle size, which can vary from 10 to 100 nm in diameter. In this review, polymeric micelles labeled with radioisotopes including technetium (99mTc) and indium (111In), and their clinical applications for several diagnostic techniques, such as single photon emission computed tomography (SPECT), gamma-scintigraphy, and nuclear magnetic resonance (NMR), were discussed. Also, micelle use primarily for the diagnosis of lymphatic ducts and sentinel lymph nodes received special attention. Notably, the employment of these diagnostic techniques can be considered a significant tool for functionally exploring body systems as well as investigating molecular pathways involved in the disease process. The use of molecular modeling methodologies and computer-aided drug design strategies can also yield valuable information for the rational design and development of novel radiopharmaceuticals.

Synthese und radioaktive Markierung potentieller PET- bzw. SPECT-Liganden zur Quantifizierung und Visualisierung der pankreatischen beta-Zell-Masse

Abstract Due to the ongoing efforts in transplanting b-cell mass there is also a great medical interest in specific b-cell imaging agents to quantify the acceptance of transplanted islets in humans in vivo. Additionally, in the context of type 1 diabetes mellitus the chronic and progressive loss of b-cells caused by autoimmune destruction has led to concerted efforts to prevent further loss of b-cells by autoantigen-specific immunotherapy of pre-diabetic patients. nateglinide and glibenclamide are SUR1 ligands used to stimulate insulin secretion in type 2 diabetic patients. They bind to a class of molecules known as the ATP-sensitive potassium channels, located on the insulin producing b-cells of the islets of Langerhans and are therefore excellent candidates as b-cell specific tracers. To obtain a precursor for a direct labelling of nateglinide with [18F]fluoride, the aromatic system of the phenylalanine structure element was derivatised to obtain a phenolic OH-group in 4-position which is capable of further derivatisation. The formed phenylether N-(trans-4-isopropylcyclohexanecarbonyl)-O-(2-hydroxyethyl)-D-tyrosin benzylester was tried to be tosylated according to several literature procedures but none of them was applicable. The catalytic influence of ytterbium(III)triflate in the reaction of toluenesulfonic acid anhydride and the alcohol was investigated. It was found that Yb(III) facilitates the tosylation of the alcohol under non-basic conditions and was extended to the tosylation of a great variety of different alcohols to prove its applicability in general. The radioactive labelling of N-(trans-4-isopropyl-cyclohexanecarbonyl)-O-(2-[18F]fluoroethyl)-D-tyrosine with [18F]F-/ Kryptofix® 222/ K2CO3-system was achieved in radiochemical yields (RCY) of 10 % after deprotection with Pd/ C and H2. In addition to the direct labelling approach, a labelling procedure applying 2[18F]fluoroethyltosylate and N-(trans-4-isopropyl-cyclohexanecarbonyl)-D-tyrosin was performed in 40 % RCY. Unfortunately the determination of the KD value of N-(trans-4-isopropylcyclohexanecarbonyl)-O-(2-fluoroethyl)-D-tyrosine revealed a significant decrease in affinity compared to original nateglinide. The in vivo evaluation of some 18F-labelled glibenclamide derivatives in humans and animals revealed that longer measuring times are warranted because a high liver uptake spoiles the data acquisition and the activity washout proceeds very slowly. Therefore glibenclamide was labelled with a radioisotope with a longer half life such as 99mTc (t1/2 = 6 h) to lengthen the possible time frame for image acquisition. The synthesis of a 99mTc labelled hydrophilic glibenclamide derivative was performed. It is hoped that gliben-clamide is internalised into the b-cell and there binds to the 95 % of intracellular SUR-1 receptors with eventual metablolisation and thus trapping in the cell. The KD-value of the corresponding Re-compound was determined to be 0.5 nM and the insulin secretion properties were similar to those of original glibenclamide. The labelling precursor N-{4-[N,N-bis-(carboxy-methyl)-aminoethyl)-5-chlorobenzene-carboxamido]-ethyl}-benzene-sulfonyl-N'-cyclohexyl urea tris sodium salt was reacted with [99mTc(I)(OH2)3(CO)3] Cl to yield the final N-{4-[99mTc(I)-tricarbonyl-N,N-bis-(carboxymethyl)-aminoethyl)-5-chloro-benzene-carboxamidoethyl]-benzene-sulfonyl}-N'-cyclo-hexyl-urea sodium salt in 70% RCY.

Synthese, Tritierung, 99m Tc-Markierung und Evaluierung von Benzamid-Derivaten zur Visualisierung der D 2, D 3-Rezeptoren

Die Diagnose und Therapie von neurodegenerativen Krankheiten, wie beispielsweise Morbus Parkinson besitzt in der heutigen Gesellschaft eine immer größere Bedeutung. Über moderne, bild¬gebende nuklear¬medizinische Verfahren wie SPECT und PET ist es mit geeigneten Radioliganden möglich, Morbus Parkinson vor dem Auftreten von Symptomen zu diagnostizieren. Ein wichtiger Ansatzpunkt zur Diagnose von Morbus Parkinson ist die Visualisierung der postsynaptischen Dopamin-Rezeptoren über radioaktiv (11C, 18F, 123I) markierte Benz¬amid-Derivate. Auf Grundlage der (S)-Pyrolidin-2,3-dimethoxy-Benzamid-Struktur des 18F-Liganden Fallypride wurden verschiedene 99mTc-markierte Benzamid-Derivate als potentielle Radio¬liganden zur Parkinson-Diagnostik entwickelt. Um das Potential von Metall-konjugierten Benzamiden abschätzen zu können, wurden zunächst einfache Vergleichssubstanzen entwickelt. Diese sollten die Einführung eines Chelators simulieren und wurden hierfür hinsichtlich ihrer in vitro-Bindungsaffinitäten zu den Dopamin-, Serotonin- und adrenergen Rezeptoren evaluiert. Die zunächst entwickelten Derivate mit unterschiedlichen Kettenlängen zur Kopplung des Chelators zeigten für die Propylkette Affinitäten im nanomolaren Bereich. Im Anschluss sollten basierend auf diesen Ergebnissen vier verschiedene Chelatoren (Carbony-Cyclopentadienyl, Amido-Cyclopentadienyl, 2-Pyridyl-Imin und N2S2) über eine Propylkette an die 5-Position der Benzamidgrundstruktur gekoppelt werden. Die geplante Synthese des Carbonyl-Cyclopentadienyl-Derivates gelang jedoch nicht. Für die weiteren Chelatoren (Amido-Cyclopentadieny, 2-Pyridyl-Imin und N2S2) konnten die jeweiligen Markierungs¬vorläufer und Rhenium-Komplexe dargestellt werden, die ebenfalls hinsichtlich ihrer Bindungs¬affinitäten evaluiert wurden. Die erzielten Affinitäten zeigten, dass eine Über¬tragung der Affinitäten der einfachen Vergleichssubstanzen auf die komplexeren Metall-Benzamide nicht möglich war. Insbesondere der N2S2-Rhenium-Komplex besitzt nur noch geringe Affinität (490 - 900 nM) zu den D2- und D3-Rezeptoren. Die mittel-affinen 2-Pyridyl-Imin- und Amdio¬cyclopentadien-Komplexe wurden mit 99mTc markiert und die Markierungsausbeute hinsichtlich Reaktionstemperatur, Markierungs-vorläuferkonzentration und Heizmethoden optimiert. Dabei konnte der Imin-Komplex quantitativ mittels fac-[99mTc(CO)3(H2O)3]+ in 30 Minuten bei 45°C markiert werden. Der Amido-Cyclopentadien-Komplex konnte über die Umsetzung des Ferrocen-Markierungsvorläufer mit Mn(CO)5Br und [99mTcO4]- in Ausbeuten von bis zu 60 % markiert werden. Im Anschluss an die Markierungen wurden die 99mTc-Komplexe über HPLC isoliert und in in vitro-Auto¬radiographien von Rattenhirnschnitten weiter evaluiert. Die erhaltenen Ergebnisse bestätigten die für die Rhenium-Komplexe erzielten Affinitäten und zeigten keine spezifische Anreicherung in bestimmten Hirnarealen. Aus diesen Ergebnissen kann ge¬schlossen werden, dass die dargestellten 99mTc-Benzamide aufgrund mangelnder Affinitäten und einer hohen unspezifischen Bindung keine geeigneten Liganden zur Darstellung der D2- und D3- Rezeptoren sind. Um die dargestellten 99mTc-Benzamide mit [18F]Fallypride vergleichen zu können, wurde zusätzlich [3H]Fallypride dargestellt. Hierfür wurde zunächst der Nor-Markierungsvor¬läufer synthetisiert und die Markierungsausbeute optimiert. Die finale Umsetzung mit [3H]Methylnosylat ergab nach HPLC-Aufreinigung 15 mCi [3H]Fallypride mit einer radio¬chemischen Reinheit von >99,5 %. Erste Autoradiographien zeigten eine hohe Anreicherung des Liganden im Striatum, verbunden mit einer sehr niedrigen unspezifischen Bindung.

Studio di fattibilità della produzione diretta di tc-99m mediante ciclotrone

Le caratteristiche del 99mTc e la possibilità per gli ospedali di produrlo in loco quotidianamente grazie ai generatori, hanno reso questo radioisotopo il più utilizzato della fisica medica: è richiesto in circa l’80% delle procedure di medicina nucleare con circa 7 milioni di somministrazioni all’anno in Europa e 8 milioni negli USA. Inoltre il campo di applicabilità del 99mTc è molto vasto: viene infatti utilizzato per scintigrafie ossee, epatiche, renali, celebrali, tiroidee e per il controllo della funzionalità epatica. A causa del notevole incremento dell’insorgenza di patologie oncologiche e dell’aumento della popolazione, la richiesta di 99mTc è sempre cresciuta negli anni ed è ancora destinata a crescere nei prossimi; l’unico fattore attenuante è lo sviluppo di altre tecniche di diagnostica funzionale come la PET ( Positron Emission Tomography ). Nonostante la creazione del 99mTc da generatori di 99Mo sia ancora oggi il metodo di produzione più efficiente, si sta ponendo recentemente la necessità di ricercare nuove tecniche di produzione dell’isotopo per soddisfare le grandi quantità richieste dal mercato globale. Questo accade perché malgrado l’utilizzo del 99mTc sia in forte crescita, la produzione di 99Mo è destinata a diminuire in quanto necessita di reattori nucleari: gli ingenti costi delle moderne centrali e le elevate quantità di scorie prodotte, stanno guidando la politica mondiale verso una denuclearizzazione che renderà in pochi anni impossibile soddisfare la richiesta di 99Mo della medicina nucleare. Questo lavoro di tesi si colloca in questo contesto, cioè nella ricerca di un metodo alternativo per la produzione di 99mTc: l’irraggiamento con protoni di un target di 100Mo arricchito, in un ciclotrone ad uso medicale. L’obbiettivo che si vuole raggiungere è fornire una stima attendibile su tale produzione, valutare la qualità dell’isotopo e mettere in luce eventuali problematiche riscontrabili.

Advanced aspects of radiation protection in the use of particle accelerators in the medical field

In this work, the well-known MC code FLUKA was used to simulate the GE PETrace cyclotron (16.5 MeV) installed at “S. Orsola-Malpighi” University Hospital (Bologna, IT) and routinely used in the production of positron emitting radionuclides. Simulations yielded estimates of various quantities of interest, including: the effective dose distribution around the equipment; the effective number of neutron produced per incident proton and their spectral distribution; the activation of the structure of the cyclotron and the vault walls; the activation of the ambient air, in particular the production of 41Ar, the assessment of the saturation yield of radionuclides used in nuclear medicine. The simulations were validated against experimental measurements in terms of physical and transport parameters to be used at the energy range of interest in the medical field. The validated model was also extensively used in several practical applications uncluding the direct cyclotron production of non-standard radionuclides such as 99mTc, the production of medical radionuclides at TRIUMF (Vancouver, CA) TR13 cyclotron (13 MeV), the complete design of the new PET facility of “Sacro Cuore – Don Calabria” Hospital (Negrar, IT), including the ACSI TR19 (19 MeV) cyclotron, the dose field around the energy selection system (degrader) of a proton therapy cyclotron, the design of plug-doors for a new cyclotron facility, in which a 70 MeV cyclotron will be installed, and the partial decommissioning of a PET facility, including the replacement of a Scanditronix MC17 cyclotron with a new TR19 cyclotron.

Outcome a lungo termine dei pazienti pediatrici con rene singolo. Valutazione di marker laboratoristici e strumentali di danno renale

Obiettivi: valutare in pazienti con rene singolo congenito la correlazione tra il filtrato glomerulare misurato con il DTPA (DTPA-VFG) e 1) marker laboratoristici di danno renale (creatinina, cistatinaC, proteinuria) 2) formule per stimare il filtrato glomerulare 3) parametri di valutazione della crescita renale ecografica. Materiali e metodi: Sono stati arruolati 118 pazienti con rene singolo congenito tra 0 e 18 anni. Sono stati valutati a ogni visita altezza, creatinina, cistatinaC, proteinuria e lunghezza ecografica renale. E’ stato calcolato il filtrato stimato con formule basate sulla creatinina (Schwartz), sulla cistatina C (Zappitelli, Filler, Grubb e Bokenkamp) e su entrambe (equazione di Zappitelli). La crescita renale è stata valutata come rapporto lunghezza ecografica/altezza corporea (USL/H), differenza percentuale tra lunghezza renale misurata e attesa per età (delta%) e presenza o meno d’ipertrofia compensatoria. In 74 bambini è stata misurata la DTPA-VFG. Risultati: Il follow-up è di 2.1 ± 0.9 anni. Il 65% sono maschi. Nessun paziente ha sviluppato danno renale cronico. La media del DTPA-VFG era di 135±44ml/min/1.73m², il valore medio della creatinina 0.47±0.17mg/dl e di cistatinaC di 1±0.4mg/L. La lunghezza ecografica renale media era di 100±17 mm, il rapporto USL/H medio di 0.8±0,1 e il delta% di 1,13±11,4, il 66% presentava ipertrofia renale. Le uniche correlazioni significative con DTPA-VFG sono inversa con la creatinina (p=<.001) e lineare con USL/H (p=<.001). Discussione: Lo studio ha mostrato che come per altre nefrouropatie, la creatina e l’ecografia renale siano due strumenti validi per il follow-up dei pazienti con rene singolo congenito. Il limite principale è dovuto al fatto che nessuno dei pazienti ha sviluppato danno renale cronico e pertanto non è stato possibile stabilire dei cutt-off di rischio per parametri quali USL/H.

Development and optimisation of novel 68 Ga-folates - towards early diagnosis of ovarian cancer

Der Folsäure-basierte Radiotracer Etarfolatide (99mTc-EC 20) hat in der Vergangenheit sehr vielversprechende Ergebnisse im Bereich der frühzeitigen Diagnostik von Ovarialkarzinomen gezeigt. Einzelphotonen-Emissionscomputertomographie (SPECT) erlaubt dabei eine Visualisierung der Krankheit in einem sehr frühen Stadium – ermöglicht wird dies durch Folsäure, welche als Target Vektor dient. Um das erfolgreiche Prinzip der Radiofolate auf die Positronen-Emissionstomographie (PET) zu übertragen, welche eine noch höhere räumliche Auflösung ermöglicht, wurden in den letzten fünf Jahren bereits 18F-folate entwickelt. Deren hepatobiliären Exkretionsmuster, verursacht durch die relativ hohe Lipophilie der Strukturen, entsprachen jedoch nicht den Anforderungen. Eine optimierte Bioverteilung der Tracer in vivo kann durch eine generelle Erhöhung der Polarität erfolgen. Die Kombination aus einem polaren 68Ga-Komplex mit Folsäure als Target Vektor stellte den Fokus dieses Projektes dar. Ziel war die Entwicklung eines Radiofolates mit der Tendenz einer raschen renalen Ausscheidung und verringerter hepatobiliärer Anreicherung. Dazu wurde Folsäure regiospezifisch über ihre y-Säure an verschiedene bifunktionelle Chelatoren (BFCs) gekoppelt. Vier verschiedene Reaktionstypen wurden gewählt und durchgeführt: Cu-katalysierte sowie Cu-freie Click Reaktion, Amindbindung und Thioharnstoff Bildung. Es wurden sechs verschiedene Derivate erhalten und mit 68Ga radiomarkiert.

Realizzazione e convalida del modello Monte Carlo di un calibratore di attività per radiofarmaci

I calibratori di attività sono strumenti molto importanti per la pratica, diagnostica e terapeutica, in medicina nucleare, perché permettono di associare ad un radiofarmaco una misura accurata dell’attività dell’isotopo in esso contenuto; questo è fondamentale in quanto l’attività della sorgente esprime la quantità di farmaco somministrata al paziente. In questo lavoro è stato sviluppato il modello Monte Carlo di un calibratore di attività ampiamente diffuso nei laboratori di radiofarmacia (Capintec CRC-15), utilizzando il codice Monte Carlo FLUKA. Per realizzare il modello si è posta estrema attenzione nel riprodurre al meglio tutti i dettagli delle componenti geometriche della camera e dei campioni delle sorgenti radioattive utilizzati. A tale scopo, la camera di ionizzazione di un calibratore è stata studiata mediante imaging TAC. Un’analisi preliminare è stata eseguita valutando il confronto tra l’andamento sperimentale dell’efficienza della camera in funzione dell’energia dei fotoni incidenti e quello ottenuto in simulazione. In seguito si è proceduto con la validazione: si sono studiati a questo proposito la risposta del calibratore in funzione dell’altezza della sorgente e i confronti tra i fattori relativi (rispetto ad una sorgente certificata di 137Cs) e le misure di confronto sono state eseguite con diverse sorgenti certificate di 133Ba, 68Ge-68Ga, 177Lu ed uno standard tarato internamente di 99mTc. In tale modo, si è ricoperto l'intero campo di interesse dei principali radionuclidi impiegati nelle applicazioni diagnostiche e terapeutiche di Medicina Nucleare. Il modello sviluppato rappresenta un importante risultato per l’eventuale determinazione di nuovi fattori di calibrazione o per un futuro studio relativo all’ottimizzazione della risposta del calibratore.

Added value of coronary artery calcium score as an adjunct to gated SPECT for the evaluation of coronary artery disease in an intermediate-risk population

The coronary artery calcium (CAC) score is a readily and widely available tool for the noninvasive diagnosis of atherosclerotic coronary artery disease (CAD). The aim of this study was to investigate the added value of the CAC score as an adjunct to gated SPECT for the assessment of CAD in an intermediate-risk population. METHODS: Seventy-seven prospectively recruited patients with intermediate risk (as determined by the Framingham Heart Study 10-y CAD risk score) and referred for coronary angiography because of suspected CAD underwent stress (99m)Tc-tetrofosmin SPECT myocardial perfusion imaging (MPI) and CT CAC scoring within 2 wk before coronary angiography. The sensitivity and specificity of SPECT alone and of the combination of the 2 methods (SPECT plus CAC score) in demonstrating significant CAD (>/=50% stenosis on coronary angiography) were compared. RESULTS: Forty-two (55%) of the 77 patients had CAD on coronary angiography, and 35 (45%) had abnormal SPECT results. The CAC score was significantly higher in subjects with perfusion abnormalities than in those who had normal SPECT results (889 +/- 836 [mean +/- SD] vs. 286 +/- 335; P < 0.0001). Similarly, with rising CAC scores, a larger percentage of patients had CAD. Receiver-operating-characteristic analysis showed that a CAC score of greater than or equal to 709 was the optimal cutoff for detecting CAD missed by SPECT. SPECT alone had a sensitivity and a specificity for the detection of significant CAD of 76% and 91%, respectively. Combining SPECT with the CAC score (at a cutoff of 709) improved the sensitivity of SPECT (from 76% to 86%) for the detection of CAD, in association with a nonsignificant decrease in specificity (from 91% to 86%). CONCLUSION: The CAC score may offer incremental diagnostic information over SPECT data for identifying patients with significant CAD and negative MPI results.

Cardiac image fusion from stand-alone SPECT and CT: clinical experience

Myocardial perfusion imaging with SPECT (SPECT-MPI) and 64-slice CT angiography (CTA) are both established techniques for the noninvasive evaluation of coronary artery disease (CAD). Three-dimensional (3D) SPECT/CT image fusion may offer an incremental diagnostic value by integrating both sets of information. We report our first clinical experiences with fused 3D SPECT/CT in CAD patients. METHODS: Thirty-eight consecutive patients with at least 1 perfusion defect on SPECT-MPI (1-d adenosine stress/rest SPECT with (99m)Tc-tetrofosmin) and 64-slice CTA were included. 3D volume-rendered fused SPECT/CT images were generated and compared with the findings from the side-by-side analysis with regard to coronary lesion interpretation by assigning the perfusion defects to their corresponding coronary lesion. RESULTS: The fused SPECT/CT images added information on pathophysiologic lesion severity in 27 coronary stenoses (22%) of 12 patients (29%) (P<0.001). Among 40 equivocal lesions on side-by-side analysis, the fused interpretation confirmed hemodynamic significance in 14 lesions and excluded functional relevance in 10 lesions. In 3 lesions, assignment of perfusion defect and coronary lesion appeared to be reliable on side-by-side analysis but proved to be inaccurate on fused interpretation. Added diagnostic information by SPECT/CT was more commonly found in patients with stenoses of small vessels (P=0.004) and involvement of diagonal branches (P=0.01). CONCLUSION: In addition to being intuitively convincing, 3D SPECT/CT fusion images in CAD may provide added diagnostic information on the functional relevance of coronary artery lesions.

Diagnostic accuracy of exercise electrocardiogram in patients with left anterior hemi-block

BACKGROUND: Left anterior hemiblock (LAHB) is the most frequent conduction abnormality, but its impact on the diagnostic accuracy of the exercise ECG has not been studied. The aim of our study was to determine the diagnostic accuracy of ST depression for predicting ischaemia in the presence of LAHB. PATIENTS: Consecutive patients with known or suspected coronary heart disease undergoing exercise ECG and 99mTc-sestamibi single photon emission computed tomography (SPECT) were included in the analysis. Patients with left bundle branch block, with changes in QRS morphology related to myocardial infarction, and patients who had undergone pharmacological stress testing were excluded. RESULTS: Of 1532 patients assessed, 567 patients qualified for the analysis. In 69 patients with LAHB, ECG stress testing had lower sensitivity (38% vs 86%) and lower negative predictive value (82% vs 92%) than in patients with normal baseline ECG. The reduction of sensitivity appeared to be similar in patients with isolated LAHB (n=43), in patients with right bundle branch block (n=39), and with bifascicular block (n=26). In contrast, the positive predictive value of the test was excellent. CONCLUSION: The diagnostic accuracy of the exercise ECG for prediction of ischaemia is reduced in patients with LAHB.