Développement d'agents radiopharmaceutiques pour la détermination des densités en récepteurs d'oestrogène (RE) dans les tumeurs du sein à l'aide de la tomographie d'émission par positrons (TEP)

Le cancer du sein est de nos jours le cancer le plus fréquemment diagnostiqué chez les femmes dans les pays industrialisés et la mammographie représente la seule méthode disponible de dépistage systématique de cette maladie. Lorsque le diagnostic de cancer est établi, les concentrations en récepteurs d'oestrogène (RE) et en récepteurs de progestérone (RP) de la lésion détectée sont déterminées lors de l'analyse d'une biopsie puisque ces paramètres pathologiques guident le clinicien dans l'élaboration de son pronostic et la planification du traitement. Toutefois, ces mesures in vitro sont limitées de par leur caractère invasif, leur sensibilité, l'hétérogénéité des densités de RE dans les tumeurs primaires, et la possible discordance du statut en RE entre la tumeur primaire et les métastases. Il est donc crucial de développer une technique non-invasive qui ne serait pas affectée par l'hétérogénéité intrinsèque de la distribution des RE au sein des tumeurs et qui permette à la fois la visualisation et la quantification in vivo des RE de la tumeur primaire et des lésions récurrentes ou métastatiques en un seul examen. La tomographie d'émission par positrons (TEP), associée à un radioligand émetteur de positron avec des caractéristiques pharmacocinétiques et métaboliques optimales, est une technique d'imagerie nucléaire analytique très sensible et non-invasive, et offre ainsi une alternative intéressante à l'analyse in vitro de la biopsie. Les études expérimentales qui ont été menées avec le 16[alpha]-[[indice supérieur 18] F]fluoroestradiol (FES), chez l'animal ou en clinique, ont en effet largement démontré la faisabilité de cette procédure. Cependant, le FES est métabolisé relativement rapidement, ce qui empêche une localisation optimale de cet agent radiopharmaceutique au niveau des sites riches en RE, et perturbe probablement l'interprétation quantitative des images obtenues lors d'un examen TEP-FES. La fluoration à la position 2 ou 4 sur le cycle aromatique de l'estradiol est connue pour ralentir sa dégradation métabolique en bloquant la formation des oestrogènes catéchols, alors que l'introduction d'un groupe 11[bêta]-méthoxy améliore en général notablement la sélectivité de liaison in vivo et diminue les biotransformations qui interviennent sur le cycle D. Nous avons donc envisagé de préparer une première série de composés, via l'ajout d'un substituant 2 ou 4-fluoro et/ou 11[bêta]-méthoxy au FES. Leurs affinités de liaison (RBA) pour le RE et différentes protéines plasmatiques, telles que l'alphafétoprotéine (AFP) et la protéine de transport des hormones stéroïdiennes sexuelles (SHBG), ont été mesurées".--Résumé abrégé par UMI

EANM guideline for harmonisation on molar activity or specific activity of radiopharmaceuticals:impact on safety and imaging quality

Abstract This guideline on molar activity (Am) and specific activity (As) focusses on small molecules, peptides and macromolecules radiolabelled for diagnostic and therapeutic applications. In this guideline we describe the definition of Am and As, and how these measurements must be standardised and harmonised. Selected examples highlighting the importance of Am and As in imaging studies of saturable binding sites will be given, and the necessity of using appropriate materials and equipment will be discussed. Furthermore, common Am pitfalls and remedies are described. Finally, some aspects of Am in relation the emergence of a new generation of highly sensitive PET scanners will be discussed

Side-by-side comparison of the two widely studied GRPR radiotracers, radiolabeled NeoB and RM2, in a preclinical setting

Introduction: NeoB and RM2 are the most investigated gastrin-releasing peptide receptor (GRPR)–targeting radiotracers in preclinical and clinical studies. Therefore, an extensive side-by-side comparison of the two radiotracers is valuable to demonstrate whether one has advantages over the other. Accordingly, this study aims to compare the in vitro and in vivo characteristics of radiolabeled NeoB and RM2 to guide future clinical studies. Method: The stability of the radiolabeled GRPR analogs was determined in phosphate buffered saline (PBS), and commercially available mouse and human serum. Target affinity was determined by incubating human prostate cancer PC-3 cells with [177Lu]Lu-NeoB or [177Lu]Lu-RM2, + / − increasing concentrations of unlabeled NeoB, RM2, or Tyr4-bombesin (BBN). To determine uptake and specificity cells were incubated with [177Lu]Lu-NeoB or [177Lu]Lu-RM2 + / − Tyr4-BBN. Moreover, in vivo studies were performed to determine biodistribution and pharmacokinetics. Finally, radiotracer binding to various GRPR-expressing human cancer tissues was investigated. Results: Both radiotracers demonstrated high stability in PBS and human serum, but stability in mouse serum decreased substantially over time. Moreover, both radiotracers demonstrated high GRPR affinity and specificity, but a higher uptake of [177Lu]Lu-NeoB was observed in in vitro studies. In vivo, no difference in tumor uptake was seen. The most prominent difference in uptake in physiological organs was observed in the GRPR-expressing pancreas; [177Lu]Lu-RM2 had less pancreatic uptake and a shorter pancreatic half-life than [177Lu]Lu-NeoB. Furthermore, [177Lu]Lu-RM2 presented with a lower tumor-to-kidney ratio, while the tumor-to-blood ratio was lower for [177Lu]Lu-NeoB. The autoradiography studies revealed higher binding of radiolabeled NeoB to all human tumor tissues. Conclusion: Based on these findings, we conclude that the in vivo tumor-targeting capability of radiolabeled NeoB and RM2 is similar. Additional studies are needed to determine whether the differences observed in physiological organ uptakes, i.e., the pancreas, kidneys, and blood, result in relevant differences in organ absorbed doses when the radiotracers are applied for therapeutic purposes.</p

[11C]acetate PET/CT Visualizes Skeletal Muscle Exercise Participation, Impaired Function, and Recovery after Hip Arthroplasty; First Results

Purpose: Based on skeletal muscle acetate physiology we aimed studying muscle function after hip arthroplasty with [11C]acetate PET. Procedures: Two male patients were investigated 3 and 12weeks after hip arthroplasty with muscle [11C]acetate PET/CT performed at rest and exercise. Median muscle SUVmean were calculated on three non-consecutive transverse PET slices. Results: The four exercise PET/CT showed, compared with rest, consistent increase in [11C]acetate uptake in active muscles contralateral to surgery. On the arthroplasty side most muscles showed symmetric activity increase under exercise both at 3 and 12weeks after surgery, but four muscles showed only minor activity increase at 3weeks. At 3months, functional recovery of the latter four muscles was observed. Conclusion: Consistent increase in [11C]acetate uptake in healthy muscles under exercise compared with rest was observed by PET/CT. Transiently impaired muscle function 3weeks after surgery recovered at 3months. These first observations merit further investigatio

Matching between regional coronary vasodilator capacity and corresponding circumferential strain in individuals with normal and increasing body weight

Background: To define the relationship between regional coronary vasodilator capacity and myocardial circumferential strain at rest in normal weight, overweight, and obese individuals with normal global left-ventricular function. Methods and Results: Myocardial blood flow at rest and during pharmacologic vasodilation was measured with 13N-ammonia PET/CT in mL/g/minute in normal weight control (CON, n=12), overweight (OW, n=10), and obese individuals (OB, n=10). In addition, resting myocardial function was evaluated as circumferential strain (Єc, %) by MRI. Global myocardial flow reserve (MFR) did not differ significantly between CON and OW (2.98±0.96 vs 2.70±0.66, P=.290), whereas it declined significantly in OB (1.98±1.04, P=.030). Further, global Єc (%) was comparable between CON, OW, and OB (−0.24±0.03, −0.23±0.02, and −0.23±0.04) but it was lowest in OB when normalized to the rate-pressure product (NЄc: −0.31±0.06, −0.32±0.05, and −0.26±0.08). When MFR of the three major coronary territories was correlated with corresponding Єc, a positive association was observed in CON (r=0.36, P=.030), in OW (r=0.54, P=.002), and also in OB when relating NЄc to coronary vascular resistance during pharmacologic vasodilation (r=−0.46, P=.010). Conclusions: Higher coronary vasodilator capacity is related to corresponding regional circumferential strain at rest in non-obese individuals, while this is also observed for reduced MFR in obesit

Structural epicardial disease and microvascular function are determinants of an abnormal longitudinal myocardial blood flow difference in cardiovascular risk individuals as determined with PET/CT

Background: The aim of this study was to determine whether epicardial structural disease may affect the manifestation of a longitudinal decrease in myocardial blood flow (MBF) or MBF difference during hyperemia in cardiovascular risk individuals, and its dependency on the flow increase. Methods and Results: In 54 cardiovascular risk individuals (at risk) and in 26 healthy controls, MBF was measured with 13N-ammonia and PET/CT in mL/g/min at rest and during dipyridamole stimulation. Computed tomography coronary angiography (CTA) was performed using a 64-slice CT of a PET/CT system. Absolute MBFs during dipyridamole stimulation were mildly lower in the mid-distal than in the mid-LV myocardium in controls (2.20±.51 vs 2.29±.51, P<.0001), while it was more pronounced in at risk with normal and abnormal CTA (1.56±.42 vs 1.91±.46 and 1.18±.34 vs 1.51±.40mL/g/min, respectively, P<.0001), resulting in a longitudinal MBF difference that was highest in at risk with normal CTA, intermediate in at risk abnormal CTA, and lowest in controls (.35±.16 and .22±.09 vs .09±.04mL/g/min, respectively, P<.0001). On multivariate analysis, log-CCS and mid-LV hyperemic MBF increase, indicative of microvascular function, were independent predictors of the observed longitudinal MBF difference (P≤.004 by ANOVA). Conclusions: Epicardial structural disease and microvascular function are important determinants of an abnormal longitudinal MBF difference as determined with PET/C

Therapeutic applications of pretargeting

Targeted therapies, such as radioimmunotherapy (RIT), present a promising treatment option for the eradication of tumor lesions. RIT has shown promising results especially for hematologic malignancies, but the therapeutic efficacy is limited by unfavorable tumor-tobackground ratios resulting in high radiotoxicity. Pretargeting strategies can play an important role in addressing the high toxicity profile of RIT. Key to pretargeting is the concept of decoupling the targeting vehicle from the cytotoxic agent and administrating them separately. Studies have shown that this approach has the ability to enhance the therapeutic index as it can reduce side effects caused by off-target irradiation and thereby increase curative effects due to higher tolerated doses. Pretargeted RIT (PRIT) has been explored for imaging and treatment of different cancer types over the years. This review will give an overview of the various targeted therapies in which pretargeting has been applied, discussing PRIT with alpha-and beta-emitters and as part of combination therapy, plus its use in drug delivery systems

Synthesis and Evaluation of ePSMA-DM1:A New Theranostic Small-Molecule Drug Conjugate (T-SMDC) for Prostate Cancer

Small-molecule drug conjugates (SMDCs) are compounds in which a therapeutic payload is conjugated to a targeting vector, for specific delivery to the tumor site. This promising approach can be translated to the treatment of prostate cancer by selecting a targeting vector which binds to the prostate-specific membrane antigen (PSMA). Moreover, the addition of a bifunctional chelator to the molecule allows for the use of both diagnostic and therapeutic radionuclides. In this way, the distribution of the SMDC in the body can be monitored, and combination therapy regimes can be implemented. We combined a glutamate-urea-lysine vector to the cytotoxic agent DM1 and a DOTA chelator via an optimized linker to obtain the theranostic SMDC (T-SMDC) ePSMA-DM1. ePSMA-DM1 retained a high binding affinity to PSMA and demonstrated PSMA-specific uptake in cells. Glutathione stability assays showed that the half-life of the T-SMDC in a reducing environment was 2 h, and full drug release was obtained after 6 h. Moreover, 100 nM of ePSMA-DM1 reduced the cell viability of the human PSMA-positive LS174T cells by &gt;85% after 72 h of incubation, which was comparable to a 10-fold higher dose of free DM1. [111In]In-ePSMA-DM1 and [177Lu]Lu-ePSMA-DM1 were both obtained in high radiochemical yields and purities (&gt;95%), with &gt;90% stability in PBS and &gt;80% stability in mouse serum for up to 24 h post incubation at 37 °C. SPECT/CT imaging studies allowed for a faint tumor visualization of [111In]In-ePSMA-DM1 at 1 h p.i., and the ex vivo biodistribution showed tumor uptake (2.39 ± 0.29% ID/g) at 1 h p.i., with the compound retained in the tumor for up to 24 h. Therefore, ePSMA-DM1 is a promising T-SMDC candidate for prostate cancer, and the data obtained so far warrant further investigations, such as therapeutic experiments, after further optimization.</p

In Vivo Evaluation of Indium-111-Labeled 800CW as a Necrosis-Avid Contrast Agent.

Current clinical measurements for tumor treatment efficiency rely often on changes in tumor volume measured as shrinkage by CT or MRI, which become apparent after multiple lines of treatment and pose a physical and psychological burden on the patient. Detection of therapy-induced cell death in the tumor can be a fast measure for treatment efficiency. However, there are no reliable clinical tools for detection of tumor necrosis. Previously, we studied the necrosis avidity of cyanine-based fluorescent dyes, which suffered long circulation times before tumor necrosis could be imaged due to low hydrophilicity. We now present the application of radiolabeled 800CW, a commercially available cyanine with high hydrophilicity, to image tumor necrosis in a mouse model. We conjugated 800CW to DOTA via a PEG linker, for labeling with single-photon emission-computed tomography isotope indium-111, yielding [ &lt;sup&gt;111&lt;/sup&gt; In]In-DOTA-PEG &lt;sub&gt;4&lt;/sub&gt; -800CW. We then investigated specific [ &lt;sup&gt;111&lt;/sup&gt; In]In-DOTA-PEG &lt;sub&gt;4&lt;/sub&gt; -800CW uptake by dead cells in vitro, using both fluorescence and radioactivity as detection modalities. Finally, we investigated [ &lt;sup&gt;111&lt;/sup&gt; In]In-DOTA-PEG &lt;sub&gt;4&lt;/sub&gt; -800CW uptake into necrotic tumor regions of a 4T1 breast tumor model in mice. We successfully prepared a precursor and developed a reliable procedure for labeling 800CW with indium-111. We detected specific [ &lt;sup&gt;111&lt;/sup&gt; In]In-DOTA-PEG &lt;sub&gt;4&lt;/sub&gt; -800CW uptake by dead cells, using both fluorescence and radioactivity. Albeit with a tumor uptake of only 0.37%ID/g at 6 h post injection, we were able to image tumor necrosis with a tumor to background ratio of 7:4. Fluorescence and radioactivity in cryosections from the dissected tumors were colocalized with tumor necrosis, confirmed by TUNEL staining. [ &lt;sup&gt;111&lt;/sup&gt; In]In-DOTA-PEG &lt;sub&gt;4&lt;/sub&gt; -800CW can be used to image tumor necrosis in vitro and in vivo. Further research will elucidate the application of [ &lt;sup&gt;111&lt;/sup&gt; In]In-DOTA-PEG &lt;sub&gt;4&lt;/sub&gt; -800CW or other radiolabeled hydrophilic cyanines for the detection of necrosis caused by chemotherapy or other anti-cancer therapies. This can provide valuable prognostic information in treatment of solid tumors