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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 (12.1-18.3% ID/g at 3 h p.i. for [(125)I]39-42) and a fast clearance from the non-target organs was observed. Also, calculated effective doses that could be delivered to tumours when using corresponding [(131)I]-labelled analogues were generally higher than 100 cGy/MBq injected (98.9-150.5 cGy/MBq for [(131)I]39-42). These results make compounds 39-42 suitable candidates for (i) PET imaging of melanoma after labelling with fluorine-18 and (ii) targeted radionuclide therapy of disseminated melanoma after labelling with iodine-131.

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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. To validate our multimodality concept, the radiosynthesis of [(18)F]56 was then optimized and this radiotracer has been successfully investigated for in vivo PET imaging of melanoma in B16F0- and B16F10-bearing mouse model. The therapeutic efficacy of [(131)I]56 was then evaluated in mice bearing subcutaneous B16F0 melanoma, and a significant slow down in tumoral growth was demonstrated. These data support further development of 56 for PET imaging ((18)F, (124)I) and targeted radionuclide therapy ((131)I) of melanoma using a single chemical structure.

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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. After labeling with a high specific activity, the biodistribution of the compound was investigated in two animal models, the mouse and the sheep. Melanotic tumor retention was observed lasting several days. We visualized the internalization of the agent inside the melanosomes by secondary ion mass spectroscopy imaging, we measured the affinity constants of [(125)I]BZ18 on a synthetic melanin model and we demonstrated a radiotoxic effect of this labeled agent on B16F0 melanoma cell culture due to its cellular internalization. From this work, [(125)I]BZ18 appeared a promising melanoma targeting agent in the nuclear medicine field.

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Nos meandros de seu percurso junto ao seu grupo social, a criança encontra-se, algumas vezes, enlaçada às redes de violência que ela herda, que sua história revela ou suscita. Violências atuadas, violências suportadas. Violações do silêncio. Em qualquer caso, reina o sofrimento. Isso porque toda situação de violência é uma situação intolerável, sobretudo quando ela é cometida com crianças. As instituições, então, quando chamadas a agir, se encarregam de impedir a violência. Mas, o inelutável da violência mostra-se freqüentemente rebelde a toda tentativa de solução. Pior, muitas vezes as instituições vão provocar ou até mesmo aumentar isso que elas procuram erradicar. Por que se existem culpáveis e uma cadeia para interromper, a violência é culpada ? Partiremos de três exemplos de transmissão ardilosa na qual a violência se deslocou: no primeiro caso, inicialmente verticalmente no seio de uma família entre gerações e, depois, horizontalmente, da família em direção a uma instituição de acolhida; no outro caso, em que a violência foi colocada em prática, em série, tanto pelos atores familiares quanto institucionais; e um último exemplo em que a violência foi feita, além de uma situação conflituosa, aos trabalhadores sociais, algumas vezes diretamente e outras indiretamente. Diante de tais constatações, não podemos evitar perguntarmos se é possível contribuir para desviar esses perniciosos encadeamentos, nos quais o inexorável é tenaz. Uma vez colocada em ação, a violência pode admitir outra coisa senão a violência? (AU)

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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. In vitro, cellular [(125)I]-BZA(2) uptake was related to the pigmentation status of the cells: higher in pigmented melanoma cell lines (M4 Beu, IPC 227, B 16) than in a nonpigmented one (M3 Dau) and nonmelanoma cell lines (MCF 7 and L 929). Two mechanisms were assessed: binding of the tracer to melanin or to sigma receptors of melanoma cells. First, the uptake of [(125)I]-BZA(2) after melanogenesis stimulation by alpha-melanocyte-stimulating hormone and l-tyrosine increased in the B 16 melanoma cell line both in vitro and in vivo according to melanin concentration. Moreover, the binding of [(125)I]-BZA(2) to synthetic melanin was dependent on melanin concentration and could be saturated. Second, no competition was evidenced on M4 Beu cells between [(125)I]-BZA(2) and haloperidol, a sigma ligand, at concentrations < or =10(-6) M. We show that the specificity and sensibility of BZA(2) as a melanoma scintigraphic imaging agent are mostly due to interactions with melanic pigments.

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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. All four compounds, particularly benzamide 3, showed accumulation in the tumor, but lower, however, than that of BZA. Moreover, high concentrations of radioactivity in other organs, namely, the liver and lung, demonstrated nonspecific tumoral uptake. In view of these results, compounds 1 2 3 4 do not appear to be suitable radiopharmaceuticals for melanoma radionuclide therapy.

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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. The drug which interacts with the pigment exhibits linewidths greater than those observed for the free drug in solution. Line-broadening of the resonance occurred for the N-methyl group of acetylcholine or N-ethyl and aromatic groups of BZ. However, linewidths associated with methanol or hippuric acid were less altered by the presence of melanin. These observations indicate the specificity of the interaction between some drug moieties and the sites of melanin. From the concentration dependence of line-broadening, the apparent equilibrium dissociation constant (K(d)) of drug interaction with melanin was approached. It seems that the residual concentration-dependent line-broadening is caused by perturbations of ligand exchange between free and bound states and by differences in magnetic susceptibility present in the sample at the pigment-interacting drug moiety interface. Taken together, these results demonstrate the utility of this technique for investigating binding drugs.

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Melanoma is a neoplasia of dramatically increasing incidence that has a propensity to spread rapidly. Early detection is fundamental and patient management requires reliable, sensitive and reproducible staging methods, such as a single examination by planar scintigraphy or single-photon emission tomography (SPET) using a radiopharmaceutical with selectivity for melanoma tissue. Among iodobenzamides reported to possess an affinity for melanoma, a new compound, N-(2-diethylaminoethyl)-2-iodobenzamide (BZA(2)), was selected for a clinical trial in view of its pharmacokinetic experimental profile in melanoma-bearing mice. Planar whole-body scintigraphy using (123)I-BZA(2) was performed in 25 patients with histologically proven cutaneous melanoma. Performance was evaluated in two groups of patients with one or more documented secondary lesions ( n=13) or with no known secondary lesions ( n=12), and results were compared with those of conventional investigation techniques. No adverse clinical or biological events were recorded. Lesions were imaged by increased tracer uptake, and good quality images were obtained 4 h after administration. After a follow-up of more than 1 year, the overall results of (123)I-BZA(2) scintigraphy on a per patient basis showed a sensitivity of 100%, a specificity of 95%, a positive predictive value of 86% and a negative predictive value of 100%. The proven secondary lesions were imaged with a sensitivity of 100% and a specificity of 91%. In seven patients with suspected metastases, the absence of (123)I-BZA(2) uptake was confirmed as true negative, and in one patient without suspected metastases, (123)I-BZA(2) scintigraphy revealed a gastric lesion. Hence eight diagnoses would have been modified by (123)I-BZA(2) scintigraphy data. (123)I-BZA(2) allowed discrimination between benign and malignant lesions and, in the case of malignancies, between those of melanomatous origin and others. This compound, which is selective for melanoma tissue, appears promising for the staging and restaging of melanoma.

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