Theranostic Approach for Metastatic Pigmented Melanoma Using ICF15002, a Multimodal Radiotracer for Both PET Imaging and Targeted Radionuclide Therapy.

Purpose: This work reports, in melanoma models, the theranostic potential of ICF15002 as a single fluorinated and iodinated melanin-targeting compound.

Methods: Studies were conducted in the murine syngeneic B16BL6 model and in the A375 and SK-MEL-3 human xenografts. ICF15002 was radiolabeled with fluorine-18 for positron emission tomography (PET) imaging and biodistribution, with iodine-125 for metabolism study, and iodine-131 for targeted radionuclide therapy (TRT).

Evaluation of two (125)I-radiolabeled acridine derivatives for Auger-electron radionuclide therapy of melanoma.

We previously selected two melanin-targeting radioligands [(125)I]ICF01035 and [(125)I]ICF01040 for melanoma-targeted (125)I radionuclide therapy according to their pharmacological profile in mice bearing B16F0 tumors. Here we demonstrate in vitro that these compounds present different radiotoxicities in relation to melanin and acidic vesicle contents in B16F0, B16F0 PTU and A375 cell lines. ICF01035 is effectively observed in nuclei of achromic (A375) melanoma or in melanosomes of melanized melanoma (B16F0), while ICF01040 stays in cytoplasmic vesicles in both cells.

Synthesis, radiofluorination, and in vivo evaluation of novel fluorinated and iodinated radiotracers for PET imaging and targeted radionuclide therapy of melanoma.

Our project deals with a multimodal approach using a single fluorinated and iodinated melanin-targeting structure and offering both imaging (positron emission tomography (PET)/fluorine-18) and treatment (targeted radionuclide therapy/iodine-131) of melanoma. Six 6-iodoquinoxaline-2-carboxamide derivatives with various side chains bearing fluorine were synthesized and radiofluorinated, and their in vivo biodistribution was studied by PET imaging in B16Bl6 primary melanoma-bearing mice. Among this series, [(18)F]8 emerged as the most promising compound.

Synthesis, radioiodination and in vivo screening of novel potent iodinated and fluorinated radiotracers as melanoma imaging and therapeutic probes.

In order to develop new iodinated and fluorinated matched-pair radiotracers for Single-Photon Emission Computed Tomography (SPECT)/Positron Emission Tomography (PET) imaging and targeted radionuclide therapy of melanoma, we successfully synthesized and radiolabelled with iodine-125 seven new derivatives, starting from our previously described lead structure 3. The relevance of these radiotracers for gamma scintigraphic imaging of melanoma in rodent was assessed. The tumoural radioactivity uptake was most often high and specific even at early time points (12.

In vivo efficacy of melanoma internal radionuclide therapy with a 131I-labelled melanin-targeting heteroarylcarboxamide molecule.

The development of alternative therapies for melanoma treatment is of great interest as long-term tumour regression is not achieved with new targeted chemotherapies on selected patients. We previously demonstrated that radioiodinated heteroarylcarboxamide ([131I]ICF01012) induced a strong anti-tumoural effect by inhibiting both primary tumour growth and dissemination process in a B16BL6 melanoma model. In our study, we show that a single injection of [131I]ICF01012 (ranging from 14.

Early detection and longitudinal monitoring of experimental primary and disseminated melanoma using [¹⁰F]ICF01006, a highly promising melanoma PET tracer.

Purpose: Here, we report a new and rapid radiosynthesis of (18)F-N-[2-(diethylamino)ethyl]-6-fluoro-pyridine-3-carboxamide ([(18)F]ICF01006), a molecule with a high specificity for melanotic tissue, and its evaluation in a murine model for early specific detection of pigmented primary and disseminated melanoma.

Methods: [(18)F]ICF01006 was synthesized using a new one-step bromine-for-fluorine nucleophilic heteroaromatic substitution. Melanoma models were induced by subcutaneous (primary tumour) or intravenous (lung colonies) injection of B16BL6 melanoma cells in C57BL/6J mice.

Single photon emission computed tomography/positron emission tomography imaging and targeted radionuclide therapy of melanoma: new multimodal fluorinated and iodinated radiotracers.

This study reports a series of 14 new iodinated and fluorinated compounds offering both early imaging ((123)I, (124)I, (18)F) and systemic treatment ((131)I) of melanoma potentialities. The biodistribution of each (125)I-labeled tracer was evaluated in a model of melanoma B16F0-bearing mice, using in vivo serial γ scintigraphic imaging. Among this series, [(125)I]56 emerged as the most promising compound in terms of specific tumoral uptake and in vivo kinetic profile.

Evaluation of new iodinated acridine derivatives for targeted radionuclide therapy of melanoma using 125I, an Auger electron emitter.

The increasing incidence of melanoma and the lack of effective therapy on the disseminated form have led to an urgent need for new specific therapies. Several iodobenzamides or analogs are known to possess specific affinity for melanoma tissue. New heteroaromatic derivatives have been designed with a cytotoxic moiety and termed DNA intercalating agents.

B16 melanoma secretomes and in vitro invasiveness: syntenin as an invasion modulator.

To characterize proteins involved in melanoma dissemination, protein profiles from B16F10 and B16Bl6 cells were compared, as only B16Bl6 cells give pulmonary metastases after subcutaneous graft. As B16F10 and B16Bl6 cells had the same invasive capacities in vitro, we wondered whether their extracellular content could be different and correlate with their metastatic properties. We have shown that B16F10 and B16Bl6 culture cell supernatants have different modulatory effects on HT1080 fibrosarcoma cell invasion in Matrigel-coated chambers.

The use of [(125)I] scintigraphic in vivo imaging in melanoma-bearing mice for a rapid prescreening of vectors to melanoma tissue.

Introduction: The use of radiolabeled molecules allows the study of in vivo biodistribution, target organs, and kinetic profile after systemic administration by 1) radioactive organ counting and 2) quantitative autoradiographic analysis of whole-body slices (WBA). However, these techniques are time- and animal consuming for several times studied. So, in vivo scintigraphic imaging should appear of interest for a first screening of compounds, as it is able to rapidly demonstrate tumoral uptake and kinetics by serial examinations in the same mice.

First preclinical imaging of primary cartilage neoplasm and its local recurrence using 99mTc-NTP 15-5 radiotracer.

Unlabelled: This study on a rat model of grade II chondrosarcoma aimed to determine whether the radiotracer N-(triethylammonium)-3-propyl-[15]ane-N5 radiolabeled with (99m)Tc ((99m)Tc-NTP 15-5), which binds to cartilage proteoglycans, has pathophysiologic validity for in vivo imaging of cartilage tumoral tissue.

Methods: We used 2 experimental approaches with the Swarm chondrosarcoma rat model: that is, a primary paratibial location and local recurrence after intralesional curettage. (99m)Tc-NTP 15-5 scintigraphy and (99m)Tc-hydroxymethylenediphosphonate ((99m)Tc-HMDP) scanning were performed at regular intervals during 50 d after tumor implantation in a paratibial location (primary model; n = 12 animals) and after intralesional curettage in a femoral condyle location (recurrence model; n = 9 animals).

Targeted radionuclide therapy of melanoma: anti-tumoural efficacy studies of a new 131I labelled potential agent.

In recent years, there has been dramatic worldwide increase in incidence of malignant melanoma. Although localised disease is often curable by surgical excision, metastatic melanoma is inherently resistant to most treatments. In this context, targeted radionuclide therapy could be an efficient alternative.

Longitudinal profiling of articular cartilage degradation in osteoarthritis by high-resolution magic angle spinning 1H NMR spectroscopy: experimental study in the meniscectomized guinea pig model.

This study assessed the 1H HRMAS NMR spectroscopic profile of articular cartilage in both physiological and osteoarthitic situations. One-dimensional and two-dimensional 1H HRMAS NMR spectra were obtained from the tibial plateau cartilage of healthy and operated (unilateral medial meniscectomy and sham surgery) guinea pigs at different stages of disease, over a 6-month period. The major osteoarthritis-induced 1H HRMAS NMR changes were an increase of the N-acetyl peak of proteoglycans (at day 20 after meniscectomy) and a decrease after day 60 as the pathology evolved.

First In Vivo SPECT Imaging of Mouse Femorotibial Cartilage Using 99mTc-NTP 15-5.

This study aimed to report the first single-photon emission computed tomographic (SPECT) imaging of articular cartilage in mice using 99mTc-NTP 15-5 radiotracer. Mice intravenously injected with 99mTc-NTP 15-5 were submitted to (1) dynamic planar imaging, (2) static planar imaging, (3) 1 mm pinhole SPECT acquisition, and (4) dissection. Tomographic reconstruction of SPECT data was performed with a three-dimensional ordered subset expectation maximization algorithm, and slices were reconstructed in three axes.

Proteomic studies of B16 lines: involvement of annexin A1 in melanoma dissemination.

To identify proteins involved in melanoma metastasis mechanisms, comparative proteomic studies were undertaken on B16F10 and B16Bl6 melanoma cell lines and their subsequent syngenic primary tumours as pulmonary metastases were present only in the mice bearing a B16Bl6 tumour. 2DE analyses followed by MALDI-TOF identification showed variations of 6 proteins in vitro and 13 proteins in vivo. Differential expressed proteins in tumours were related to energy production and storage.

Melanoma affinity in mice and immunosuppressed sheep of [(125)I]N-(4-dipropylaminobutyl)-4-iodobenzamide, a new targeting agent.

The increasing incidence of melanoma and the lack of effective therapy have prompted the development of new vectors, more specific to the pigmented tumor, for early detection and treatment. Targeted agents have to exhibit a rapid, high tumor uptake, long tumor retention and rapid clearance from nontarget organs. This joint work presents results obtained with a new melanoma targeting agent, [(125)I]-N-(4-dipropylaminobutyl)-4-iodobenzamide or [(125)I]BZ18.

Development of a high-performance liquid chromatographic method for the determination of a new potent radioiodinated melanoma imaging and therapeutic agent.

N-(2-diethylaminoethyl)-6-iodoquinoxaline-2-carbamide (ICF 01012) is a new melanoma imaging agent showing promising properties for application in internal radionuclide therapy. We developed an analytical protocol for detection of ICF 01012 in biological samples using HPLC. The proposed method was first validated using standard of ICF 01012 and four potent metabolites of this compound and then applied to follow the metabolic fate of [(125)I]ICF 01012 after injection in melanoma-bearing mice.

Design, synthesis and preliminary biological evaluation of acridine compounds as potential agents for a combined targeted chemo-radionuclide therapy approach to melanoma.

Various iodo-acridone and acridine carboxamides have been prepared and evaluated as agents for targeted radionuclide and/or chemotherapy for melanoma, due to their structural similarity to benzamides which are known to possess specific affinity for melanin. Three of these carboxamides selected for their in vitro cytotoxic properties were radioiodinated with [(125)I]NaI at high specific activity. Biodistribution studies carried out in B16F0 murine melanoma tumour-bearing mice highlighted that acridone 8f and acridine 9d, presented high, long-lasting tumour concentrations together with an in vivo kinetic profile favourable to application in targeted radionuclide therapy.

Evaluation of radiolabeled (hetero)aromatic analogues of N-(2-diethylaminoethyl)-4-iodobenzamide for imaging and targeted radionuclide therapy of melanoma.

Targeted radionuclide therapy using radioiodinated compounds with a specific affinity for melanoma tissue is a promising treatment for disseminated melanoma, but the candidate with the ideal kinetic profile remains to be discovered. Targeted radionuclide therapy concentrates the effects on tumor cells, thereby increasing the efficacy and decreasing the morbidity of radiotherapy. In this context, analogues of N-(2-diethylaminoethyl)-4-iodobenzamide (BZA) are of interest.

Early detection and monitoring of cartilage alteration in the experimental meniscectomised guinea pig model of osteoarthritis by 99mTc-NTP 15-5 scintigraphy.

Purpose: This study in the meniscectomised guinea pig aimed to demonstrate that the radiotracer (99m)Tc-NTP 15-5 would have pathophysiological validity for in vivo osteoarthritis imaging.

Methods: The specificity of (99m)Tc-NTP 15-5 for cartilage was determined in healthy animals (n = 13), by tissue radioactivity counting, joint autoradiography and scintigraphy. (99m)Tc-NTP 15-5 scintigraphy was performed at 20, 50, 80, 115, 130, 150 and 180 days after medial meniscectomy (n = 10 MNX) or sham operation (n = 5), and scintigraphic ratios (operated/contralateral) were calculated for femoral (F) and tibial (T) areas.

Secondary ion mass spectrometry as a tool for investigating radiopharmaceutical distribution at the cellular level: the example of I-BZA and (14)C-I-BZA.

Unlabelled: Further development of nuclear medicine for imaging and internal radiotherapy demands a precise knowledge of the tissue and cellular distribution of radiopharmaceuticals. Ion microscopy (secondary ion mass spectrometry [SIMS]) may be particularly useful in this respect. We used SIMS to study the biodistribution of the melanoma-targeting molecule N-(2-diethylaminoethyl)-4-iodobenzamide (I-BZA), both in its native state and radiolabeled with (14)C.

Uptake in melanoma cells of N-(2-diethylaminoethyl)-2-iodobenzamide (BZA2), an imaging agent for melanoma staging: relation to pigmentation.

N-(2-diethylaminoethyl)-2-iodobenzamide (BZA(2)) has been singled out as the most efficacious melanoma scintigraphy imaging agent. Our work was designed to assess the mechanisms of the specific affinity of the radioiodinated iodobenzamide for melanoma tissue. We studied the cellular uptake and retention of [(125)I]-BZA(2) on various cell lines.

Synthesis, in vitro binding and biodistribution in B16 melanoma-bearing mice of new iodine-125 spermidine benzamide derivatives.

In the course of our investigations aimed at improving the biological characteristics of iodobenzamides for melanoma therapeutic applications, four new derivatives containing a spermidine chain have been prepared and radiolabeled with (125)I. In vitro studies showed that all compounds displayed high affinity for melanin superior to the reference compound BZA, thus validating our experimental approach. In vivo biodistribution was investigated in B16 melanoma-bearing mice.

High resolution magic angle spinning NMR spectroscopy used to investigate the ability of drugs to bind to synthetic melanin.

Iodobenzamides are known to possess an affinity for melanoma tissue dependent on tumor pigmentation. In order to investigate the molecular interactions of drugs with melanin in vitro, a synthetic pigment swelled in deuterium buffer at physiological pH was used. The spectra of various mixtures of each Iodobenzamide (BZ) with melanin were studied at 25 degrees C by NMR under MAS conditions.

Antineoplastic potency of arylchloroethylurea derivatives in murine colon carcinoma.

In a search for new antineoplastic agents the lead compound N-(4-tert-butylphenyl)-N'-(2-chloroethyl)urea (CEU-22) of a series of 1-aryl-3-(2-chloroethyl)ureas and its iodinated bioisostere CEU-98, were previously selected on the basis of their cytotoxicity and the potent tropism for the intestinal tract (evidenced for CEU-22). In this study, we investigated the antitumour profile of these two drugs for the indication of colon cancer. In vitro, we found that micromolar concentrations of both CEU-22 and CEU-98 inhibited proliferation of DLD-1, Caco-2, HT-29, SW-948 and CT-26 lines.