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

Exploring macrocyclization strategies to design novel octreotate-based radioconjugates

Peptides derived from the cyclic tetradecapeptide somastostatin exhibit a strong affinity primarily towards the G-protein coupled somatostatin receptor subtype 2 (SSTR2), which is overexpressed in neuroendocrine tumors. These somatostatin analogs, such as octreotide (TOC) or octreotate (TATE), are typically cyclized through a disulfide bridge. To address the potential fragility of this linkage in vivo, four distinct stapling strategies were explored to develop novel TATE derivatives with improved stability. Each approach induced a different distance between the two sulfhydryl groups involved into the macrocyclization. Additionally, the stapling linkers were designed to present a third functional group required for the regioselective insertion of a metal chelate. Ultimately, six stapled octreotate derivatives (stTATE-01/06), possessing 3 to 6 chemical bonds between the two cysteine residues, were synthesized and radiolabeled with indium-111. Evaluation of their affinity to SSTR2, conducted through a competitive binding assay, aimed to identify the most effective stapling strategy. However, a significant loss of affinity was observed for all stapled peptides compared to the gold standard DOTA-TATE, confirming that these macrocyclization approaches were detrimental to the biological activity of the new SSTR2 ligands.</p

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

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

eTFC-01:a dual-labeled chelate-bridged tracer for SSTR2-positive tumors

Background: Integrating radioactive and optical imaging techniques can facilitate the prognosis and surgical guidance for cancer patients. Using a single dual-labeled tracer ensures consistency in both imaging modalities. However, developing such molecule is challenging due to the need to preserve the biochemical properties of the tracer while introducing bulky labeling moieties. In our study, we designed a trifunctional chelate that facilitates the coupling of the targeting vector and fluorescent dye at opposite sites to avoid undesired steric hindrance effects. The synthesis of the trifunctional chelate N3-Py-DOTAGA-(tBu)3 (7) involved a five-step synthetic route, followed by conjugation to the linear peptidyl-resin 8 through solid-phase synthesis. After deprotection and cyclization, the near-infrared fluorescent dye sulfo-Cy.5 was introduced using copper free click chemistry, resulting in eTFC-01. Subsequently, eTFC-01 was labeled with [111In]InCl3. In vitro assessments of eTFC-01 binding, uptake, and internalization were conducted in SSTR2-transfected U2OS cells. Ex-vivo biodistribution and fluorescence imaging were performed in H69-tumor bearing mice. Results: eTFC-01 demonstrated a two-fold higher IC50 value for SSTR2 compared to the gold standard DOTA-TATE. Labeling of eTFC-01 with [111In]InCl3 gave a high radiochemical yield and purity. The uptake of [111In]In-eTFC-01 in U2OS.SSTR2 cells was two-fold lower than the uptake of [111In]In-DOTA-TATE, consistent with the binding affinity. Tumor uptake in H69-xenografted mice was lower for [111In]In-eTFC-01 at all-time points compared to [111In]In-DOTA-TATE. Prolonged blood circulation led to increased accumulation of [111In]In-eTFC-01 in highly vascularized tissues, such as lungs, skin, and heart. Fluorescence measurements in different organs correlated with the radioactive signal distribution. Conclusion: The successful synthesis and coupling of the trifunctional chelate to the peptide and fluorescent dye support the potential of this synthetic approach to generate dual labeled tracers. While promising in vitro, the in vivo results obtained with [111In]In-eTFC-01 suggest the need for adjustments to enhance tracer distribution.</p

eTFC-01:a dual-labeled chelate-bridged tracer for SSTR2-positive tumors

Background: Integrating radioactive and optical imaging techniques can facilitate the prognosis and surgical guidance for cancer patients. Using a single dual-labeled tracer ensures consistency in both imaging modalities. However, developing such molecule is challenging due to the need to preserve the biochemical properties of the tracer while introducing bulky labeling moieties. In our study, we designed a trifunctional chelate that facilitates the coupling of the targeting vector and fluorescent dye at opposite sites to avoid undesired steric hindrance effects. The synthesis of the trifunctional chelate N3-Py-DOTAGA-(tBu)3 (7) involved a five-step synthetic route, followed by conjugation to the linear peptidyl-resin 8 through solid-phase synthesis. After deprotection and cyclization, the near-infrared fluorescent dye sulfo-Cy.5 was introduced using copper free click chemistry, resulting in eTFC-01. Subsequently, eTFC-01 was labeled with [111In]InCl3. In vitro assessments of eTFC-01 binding, uptake, and internalization were conducted in SSTR2-transfected U2OS cells. Ex-vivo biodistribution and fluorescence imaging were performed in H69-tumor bearing mice. Results: eTFC-01 demonstrated a two-fold higher IC50 value for SSTR2 compared to the gold standard DOTA-TATE. Labeling of eTFC-01 with [111In]InCl3 gave a high radiochemical yield and purity. The uptake of [111In]In-eTFC-01 in U2OS.SSTR2 cells was two-fold lower than the uptake of [111In]In-DOTA-TATE, consistent with the binding affinity. Tumor uptake in H69-xenografted mice was lower for [111In]In-eTFC-01 at all-time points compared to [111In]In-DOTA-TATE. Prolonged blood circulation led to increased accumulation of [111In]In-eTFC-01 in highly vascularized tissues, such as lungs, skin, and heart. Fluorescence measurements in different organs correlated with the radioactive signal distribution. Conclusion: The successful synthesis and coupling of the trifunctional chelate to the peptide and fluorescent dye support the potential of this synthetic approach to generate dual labeled tracers. While promising in vitro, the in vivo results obtained with [111In]In-eTFC-01 suggest the need for adjustments to enhance tracer distribution.</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