A radioiodinated 7alpha-O-iodoallyl diprenorphine for mapping opioid receptors.

The aim of the current research has been to validate an original radioiodinated diprenorphine (DPN) derivative suitable for imaging studies of opioid receptors. [(125)I]7alpha-O-iodoallyl diprenorphine (7alpha-O-IA-DPN) was prepared by radioiododestannylation and in vitro and in vivo opioid receptor binding assays were performed with CDF1 mouse brains. In vitro binding studies showed high affinity (K(i)= 0.4 +/- 0.2 nM) for mouse brain membranes. In vivo studies showed 63% specific binding. Ex vivo autoradiography of brain sections confirmed high uptake and retention of [(125)I]7alpha-O-IA-DPN in regions rich in opioid receptors. This new radioiodinated DPN analogue appears to be a potential radioprobe for in vivo visualization of human cerebral opioid receptors with single photon emission computed tomography (SPECT).

Evaluation of [125I]7 alpha-O-iodoallyl diprenophine as a new potential SPECT opioid receptor imaging agent.

A new iodinated diprenorphine analog, [125I]7 alpha-O-iodoallyl diprenorphine ([125I]7 alpha-O-IA-DPN), was prepared by iododestannylation and characterized. As an opioid antagonist, this agent showed very high affinity (Ki = 0.4 +/- 0.2 nM) and 63% of specific binding by in vitro and in vivo binding studies. Inhibition curves indicated that this tracer labeled with the same affinities to three opioid receptors (mu = delta = kappa). The findings demonstrate that this proposed compound appears to be potential radioprobe for future study of opioid receptors by in vivo SPECT.

[Simulation study of the influence of collimator defects on the uniformity of scintigraphic images]. / Etude en simulation de l'influence des défauts des collimateurs sur l'uniformité des images scintigraphiques.

The mechanical tolerances in building collimators for scintillation cameras are studied. A simulation method has been used to quantify the effects of defects in hole inclination and hole diameter on the uniformity of planar and tomographic images. The calculation takes into account the geometry of the hexagonal hole collimator, the camera intrinsic resolution, the object size, the pixel size, the effect of low-pass filtering, as well as the type, size and position of the defect. For instance, a 0.03 mm diameter defect on several holes located in the central region of a very high resolution collimator can result in a 12% uniformity artefact in tomographic imaging of an 18 cm diameter cylinder, using a 3.45 mm resolution camera, 4.5 mm pixel size, and Hamming filtering with a Nyquist frequency cut-off. A 0.17 degree inclination defect of a few holes can result in the same uniformity artefact. These results show that the building of a collimator has to be very precise.

[Prospective survey on adverse effects of radiopharmaceuticals]. / Enquête prospective sur les effets indésirables des médicaments radiopharmaceutiques.

In France, radiopharmaceuticals have been considered as drugs since 1992. Few adverse reactions with radiopharmaceuticals were described in the literature. Some authors have reported a rate of 1 to 6 reactions per 100,000 injections. The purpose of the present study was to evaluate the prevalence of radiopharmaceutical-induced side effects. A prospective survey was performed from November 1993 to May 1995 (during 18 months) in the Department of Nuclear Medicine of the University Hospital in Toulouse. There were 14,794 injections of radiopharmaceuticals (99mTc-phytate, 99mTc-microspheres of serum albumin, 99mTc-dimercapto-succinic acid (DMSA), 99mTc-hydroxymethyldiphosphonate (HMDP), 99Tc-colloid, 99mTc, 99mTc-sestamibi, Thallium-201). Three side effects were reported: one case of necrosis at the injection site, one case of vomiting and one case of dizziness. All the cases occurred with Tc99m-pyrophosphate. According to the WHO definition, the first side effect was classified as 'serious'. The causal relationship was unlikely for the first and second case and probable for the third. The outcome of these side effects was always favorable.

[Characterization of the response of hexagonal parallel-hole collimators of scintillation cameras]. / Caractérisation de la réponse des collimateurs à trous parallèles hexagonaux des caméras à scintillation.

This paper presents a formulation of the frequency response of hexagonal parallel-hole collimator scintillation cameras. To describe this response, we propose an equation determined semi-empirically from a great number of simulations. The utility of the equation is that it enables the simple calculation of the response from collimator characteristics by taking into account the collimator's hexagonal structure. Because the equation does not assume translation invariance, the results can be directly compared with experimental measurements obtained with a point source. It is particularly interesting for collimators with large holes, like the medium-resolution ones used for high-energy radiation. Quality control and physical performance measurements are thus facilitated for this kind of collimator. Also, we present a new parameter that gives a quantitative assessment of the importance of partition penetration. This parameter is measured directly from the collimator frequency response. It has been studied by simulation, taking into account gamma photon attenuation in collimator partitions. The experimental measurements that have been made are in accord with the proposed equations.

Technetium labeling of bi, tri and tetradentate ligands derived from 2-aminocyclopentene-1-dithiocarboxylic acid: characterization and biodistribution of their oxo and nitrido 99mtechnetium complexes.

We have synthesized and characterized seven ligands derived from 2-aminocyclopentene-1-dithiocarboxylic acid with different donor sets (SN2-, SNO2-, SNN2-, SNNO3- and SNNN3-) and different substituents on the sulfur moieties-SR (with R = H, CH3 or C2H5O(CH3)CH). With five of these ligands technetium nitrido complexes have been obtained with high yields (over 95%) using rather harsh conditions (pH = 1, temperature > or = 80 degrees C), whereas for technetium oxo complexes similar high yields were only obtained with two ligands but with mild conditions (pH = 7-8, temperature approximately equal to 50 degrees C). Changing an OH group for an NH2 has a drastic effect upon labeling yields. The possibility of complexing ligands as either oxo (TcO)3+ or nitrido (TcN)2+ derivatives increases the number of available labeled agents with different overall change and consequently with different biological behavior.

Synthesis, characterization and biodistribution of a new technetium-99m complex with trimethylsilylmethylisonitrile. Comparison with 99mTc-TBI and 99mTc-MIBI.

An isonitrile ligand with a silicium component was synthesized and a copper salt of this ligand was then used to form a 99mTc complex. We evaluated the physicochemical characteristics of the complex and its biodistribution in rat. The chemical properties, i.e. lipophilic affinity and charge, were comparable to those of other 99mTc complexes formed with similar isonitrile compounds (99mTc-MIBI and 99mTc-TBI). In contrast, the tissue biodistribution of this new technetium complex differed markedly, as it was mainly taken up in the liver and not at all in the heart.

In vivo binding of [125I]NH2-carfentanil to mu opioid receptors in mouse brain.

A functionalized derivative of the mu opioid agonist carfentanil was synthesized (NH2-carfentanil) and showed high specific activity when radiolabeled with iodine. [127I]NH2-carfentanil displayed high affinity and pronounced mu-binding selectivity with a delta/mu selectivity ratio of over 1200. The ability of [125I]NH2-carfentanil to interact in vivo with opioid receptors was determined in mouse brain using ex vivo binding techniques. Twenty minutes after intraperitoneal injection, 0.1% of the [125I]NH2-carfentanil injected into the mouse was present in the brain. [125I]NH2-carfentanil specific binding was inhibited by co-injection of naloxone or morphine while naltrindole, a delta-selective antagonist, was unable to displace the bound radioligand. Autoradiographic experiments revealed a heterogeneous distribution of [125I]NH2-carfentanil specific binding sites, maximal binding occurred in areas with high densities of mu receptors. Peripherally administered iodo-NH2-carfentanil selectively labelled central mu opioid receptors in mouse indicating great potential for single photon emission computed tomography studies.

Synthesis, characterization and biodistribution of new 99mTc oxo and nitrido complexes with bi- and tetradendate unsaturated NS and N2S2 Schiff bases derived from 2-aminocyclopentene-1-dithiocarboxylic acid as potential heart imaging agents.

The synthesis, characterization and 99mTc labelling of unsaturated diamino dithiol ligands with methyl dithiocarboxylate functions: 2-aminocyclopentene-1-dithiocarboxylic methyl ester (H2L1), N,N'-ethylene bis(methyl 2-aminocyclopentene-1-dithiocarboxylate) (H2L2) and N,N'-propylene bis (methyl 2-aminocyclopentene-1-dithiocarboxylate) (H2L3) are described. Cationic oxo (Tc = O) and neutral nitrido (Tc = N) complexes were obtained. Biodistribution studies in rat showed a good heart uptake of 99mTcN-L2 (2% ID at 5 min) with a high heart-to-blood ratio (5.8 at 5 min), but this complex also exhibited high lung and liver uptake.

Synthesis, characterization and biodistribution of new 99mTc Oxo and nitrido complexes of unsaturated tetradentate (N2S2)ligands.

Three unsaturated Schiff base tetradentate (N2S2 or N2SO) ligands were synthesized and characterized. Oxo and nitrido 99m-technetium complexes were obtained with these ligands. The nitrido complexes were formed using a new easy method available as a kit. When injected into rats and mice, these lipophilic complexes were able to cross the blood-brain barrier but brain perfusion imaging could not be performed due to the insufficient uptake and retention time.

[A simulation method for studying scintillation camera collimators]. / Une méthode d'étude par simulation des collimateurs des caméras à scintillation.

This paper presents a computer simulation of photon interaction with collimator septa, which allows the point spread function of scintillation camera collimators to be calculated. The method simulates photon attenuation along their propagation direction in a determinist way. Using this simulation, the spatial resolution, geometric efficiency and penetration index of collimators may be easily assessed. Results obtained with this method are presented and compared with those obtained from standard formulae. We show the usefulness of the simulation which precisely accounts for effects of septum penetration. Measurements performed on two collimators with 131I and 99Tcm point sources provide results consistent with those obtained from the simulation method. In conclusion we show that this method is an accurate tool to assist conception of collimators for nuclear medicine.

Prone decubitus: a solution to inferior wall attenuation in thallium-201 myocardial tomography.

We propose an efficient method to suppress inferior wall attenuation in 201TI 180 degrees myocardial tomography. We systematically performed redistribution studies in both supine and prone decubitus, assuming that the latter should result in shifting with respect to each other's cardiac structures and diaphragm as well as subphrenic organs possibly responsible for attenuation. The comparison of both studies in 25 normal subjects by visual interpretation and circumferential profiles analysis showed a complete suppression of significant attenuation in the inferior wall in prone studies. In addition and consequently, the standard deviation of activity in this area was markedly reduced and became close to its value in anterior and lateral walls. This simple technique now routinely performed in over 400 patients drastically improves specificity in the evaluation of inferior wall abnormalities by suppressing attenuation artifacts and, incidently, the effect of high individual variability in left phrenic and subphrenic anatomic configuration.

Human brain and spinal cord scan after intracerebroventricular administration of iodine-123 morphine.

[123I]iodomorphine (IMPH) was administered intracerebroventriculary (i.c.v.) in eight patients treated by i.c.v. morphinotherapy (i.c.v.m.). Scans obtained by gamma-scintigraphy over 1 h post-injection showed only a slight diffusion of IMPH beyond the ventricular system, particular attention being paid to the spinal cord. These data agree well with induced i.c.v.m. analgesia (mean latency 20 min) and biological results such as HPLC assay of morphine in the lumbar cerebrospinal fluid, supporting the action of morphine only on the central opiate receptors.

Influence of the menopause and aging on spinal density in French women.

Dual photon absorptiometry (DPA) was used to measure the bone mineral density (BMD) of the lumbar spine in 510 normal women from the south of France. Long-term precision was 2.2%. BMD was stable in young adults and again in women over 70 years of age. Perimenopausal women at an average age of 51 years already evidenced a slight bone diminution (5%) compared to young adults and women within 2 years of the menopause already had a 10% diminution. The average rate of apparent bone loss in this cross-sectional study was 1% per year from age 45 to 65 years, but about 75% of this decrease occurred in the first decade after the menopause. Spinal BMD in our normal French population appears to be 5-10% lower than US values.

[Acupuncture meridians demythified. Contribution of radiotracer methodology]. / Les méridiens d'acupuncture démythifiés. Apport de la méthodologie des radiotraceurs.

Radioactive trajectories can be visualized by injecting a radioactive tracer, technetium 99 m, at the site of acupuncture points. To determine the exact nature of these trajectories we performed several experiments on healthy volunteers, and our results may be summarized as follows. The target organs of technetium 99 m, and notably the thyroid gland, were always visualized. The circulating radioactivity, visible on scintiscans and confirmed by venous blood counts, was not negligible. The radioactive trajectories we observed were often divided at their starting point and did not extend along the whole length of the acupuncture meridians they might have made visible. The radioactive trajectories disappeared after venous blockade to reappear when the blockade was lifted. Finally, the radioactive trajectories obtained were very similar after injection at the acupuncture point and at a control point. These findings indicate a lymphatic and venous drainage of the radioactive tracer at the site of injection followed by transportation through the veins, rather than visualization of acupuncture meridians as suggested by some authors.

[Quantitative renal scintigraphy with technetium-labelled dimercaptosuccinic acid in children]. / Scintigraphie rénale quantitative à l'acide dimercaptosuccinique marqué. Chez l'enfant.

Separate measurement of renal function is essential in children with urinary tract disease. This can be done satisfactorily by means of kidney scintigraphy with technetium 99m-labelled dimercaptosuccinic acid. A retrospective study of the records of 415 children, which comprised renal function tests, radiology and scintigraphy, confirmed the value of the radioisotope technique. Graphs of height, kidney uptake and kidney uptake density in relation to age were established, showing highly significant correlations with renal function tests and intravenous urography results, but many dissociations were encountered. Separate renal function evaluation by radioisotope scintigraphy seems to be more reliable than evaluation extrapolated from measurement of the cortical areas at intravenous urography. In vesico-ureteral reflux scintigraphy makes it possible to detect reflux nephropathy at an earlier stage than with other methods.

[An experimental model of osteoarthritis. II.- Biochemical study of collagen and proteoglycans]. / Etude d'un modèle expérimental d'arthrose. II.-Etude biochimique du collagène et des protéoglycanes.

We investigated biochemical modifications of the initial phase of cartilage degradation in an osteoarthritic model developed in the rabbit by intraarticular papain injection. The amino-acid composition of the collagen did not differ significantly between control and papain-treated groups. After 3H-proline in vivo incorporation, the absence of radioactivity in peaks beta 12 and alpha 2 shows that cartilage did not synthesize type I collagen in noticeable quantity during the labelling period. The study of proteoglycans by the use of the "fixed charges density" (FCD) shows that in our model they decreased rapidly and substantially, as in human disease. The decrease was measurable from 1 h after injection with a minimum at about 24 h (54% of the normal level). However, increased 35SO4 incorporation was observed, beginning very soon after injection and passing through a maximum (500% of the normal level) around the 3rd day. The rates of 3H-proline incorporation and 3H-hydroxyproline formation were decreased in the treated cartilage in a similar way as for the proteoglycans, with a minimum (55% of the normal level) at about 24 h. The "turn-over" of 3H-hydroxyproline and "non collagen" 3H-proline were increased in the treated cartilage. The half-lives of both amino-acids went respectively from 26 to 15 days and from 14 to 10 days. Injection of papain in the rabbit knee-joint produced a major loss of ground substance and a reaction of the chondrocytes. The cells metabolism seemed modified with especially a catabolism stimulation.

[An experimental model of osteoarthritis. I. Induction and ultrastructural study]. / Etude d'un modèle expérimental d'arthrose. I.--Induction et étude ultrastructurale.

Starting from Bentley's works [2], we elaborated an experimental model of arthrosis easy to use, providing reproducibility of effects and showing the same development as the human disease, but within a far shorter time. Papain injection induced a quick, high loss in proteoglycans. A rapid, localised chondrocyte reaction in the middle layer of the support area was noted. In this area, cells rapidly showed hyperactivity signs and a crown of microfibers taking the amyloid tissue-specific staining was seen around them. The building of such crowns might result from a discrepancy between collagen and proteoglycan secretion inducing a modification in their inter-relations. We also noticed binucleate cells, someones being in process of division, which might be the beginning of clones.

Pharmacokinetics of arginine and aspartic acid administered simultaneously in the rat--III: Changes in the levels of amino acids in the plasma, liver and brain after simultaneous administration of arginine and aspartic acid.

Changes in the levels of amino acids in the plasma, liver and brain were studied in rats after simultaneous administration of 0.1 mmol/rat of arginine and aspartic acid. The levels of most of the assayed amino acids underwent various changes some of which only occurred in one of the organs studied, for example, GABA in the brain and proline in the liver. It is difficult to advance any explanation. Meanwhile some of changes can be explained on the grounds of well-known metabolic changes. The large increase of ornithine in the liver may be due to the action of arginase in the first stage in the urea cycle. This amino acid is the precursor of glutamic acid and proline which may explain the high levels of these two amino acids observed especially in the liver. The increase of GABA in the brain may be due to the simultaneous administration of arginine and aspartic acid which could induce the formation of ornithine and alpha-ketoglutaric acid respectively, two metabolites known to increase cerebral GABA. The increases in Ser, Gly, and Ala observed in practically all the tissues studied may be due to the formation of oxaloacetate from aspartic acid.