Synthesis of Gd and (68)Ga complexes in conjugation with a conformationally optimized RGD sequence as potential MRI and PET tumor-imaging probes.

We report the synthesis of novel chelates of Gd and (68)Ga with DPTA, DOTA, HP-DOA3, as well as with AAZTA, a novel chelating agent developed by our research group. These chelating agents were appropriately conjugated, prior to metal complexation, with DB58, an RGD peptidomimetic, conformationally constrained on an azabicycloalkane scaffold and endowed with high affinity for integrin α(ν)ß(3) . Because α(ν)ß(3) is involved in neo-angiogenesis in solid tumors and is also directly expressed in cancer cells (e.g. glioblastomas, melanomas) and ovarian, breast, and prostate cancers, these constructs could prove useful as molecular imaging probes in cancer diagnosis by MRI or PET techniques. Molecular modeling, integrin binding assays, and relaxivity assessments allowed the selection of compounds suitable for multiple expression on dendrimeric or nanoparticulate structures. These results also led us to an exploratory investigation of (68)Ga complexation for the promising (68)Ga-PET technique; the AAZTA complex 15((68)Ga) exhibited uptake in a xenograft model of glioblastoma, suggesting potentially useful developments with new probes with improved affinity.

Investigation of the longitudinal relaxation rate of blood after gadobenate dimeglumine administration: sequence optimization, dynamic acquisition, and clinical impact for contrast-enhanced MR angiography of the carotid arteries.

OBJECTIVES: To optimize the image acquisition parameters for improved steady-state (SS) contrast-enhanced magnetic resonance angiography (CE-MRA) of the carotid arteries with gadobenate dimeglumine. MATERIALS AND METHODS: An inversion recovery fast low-angle shot (IR-FLASH) sequence for ultrafast determination of the longitudinal relaxation rate R1 was first optimized on phantoms and tested against a routine variable repetition time (TR) spin echo sequence used as reference standard. Different combinations of flip angle (FA, between 6 and 14 degrees) and inversion time (between 134 and 9000 milliseconds) were evaluated to achieve the best trade off between speed and accuracy. The optimized sequence was thereafter used in vivo in 5 subjects to determine the time evolution of blood R1 at 1.5 T after administration of gadobenate dimeglumine at 0.1 mmol/kg bodyweight. An optimal FA for angiographic measurement was thereafter derived from the Ernst equation based on experimental values of R1 previously determined in vivo. Finally, steady-state CE-MRA examinations were performed in 20 subjects to evaluate the improved contrast achieved after optimization of the FA for maximal blood signal enhancement. RESULTS: An ultrafast IR-FLASH sequence with a flip angle of 8 degrees and a properly defined set of inversion time values was shown to give in vitro R1 determinations that were in good agreement with those obtained using a routine, time consuming, variable-TR spin echo sequence. The use of this ultrafast IR-FLASH sequence in vivo allowed the blood signal behavior in the carotid arteries after gadobenate dimeglumine administration to be monitored. Using this sequence, the R1 decreased from 8.7±0.96 s⁻¹ at 30 seconds after injection to 3.8±0.24 s⁻¹ at 10 minutes after injection. Based on these data for R1, the optimal FA for SS CE-MRA was calculated to be 18 degrees for a gradient echo acquisition protocol with TR=7.5 milliseconds, when gadobenate dimeglumine is used. Significantly higher blood signal to noise ratio was achieved on SS images acquired using a three-dimensional spoiled gradient echo sequence with a FA of 18 degrees than on corresponding images acquired with a FA of 35 degrees as used typically for intravascular blood pool contrast agents (52.5±8.3 vs. 29.5±6.0; P<0.05, Mann-Whitney U test). CONCLUSION: Detailed experimental knowledge of the in vivo R1 behavior of blood after gadobenate dimeglumine injection and appropriate modification of the acquisition parameters enables improved signal intensity enhancement on steady-state CE-MRA of the carotid arteries.

Testosterona sérica en enfermedades metabólicas crónicas y categorización del hipogonadismo bioquímico / Testosterone deficiency in chronic metabolic diseases and categorization of biochemical hypogonadism

Las enfennedades metabólicas crónicas (EMC) constituyen las principales causas de morbimortalidad en adultos y en el varón se asocian a las alteraciones biológicas debida al déficit de testosterona (T) del envejecimiento (Síndrome de ADAM). Se analizan de forma transversal los niveles séricos de T total, como parámetro biológico de función androgénica, en 235 pacientes afectos de diabetes mellitus tipo 2 (DM2, n= 173), dislipidemia (DLP, n=42), obesidad (OB, n=20) y 31 individuos control; comparando según la edad, índíce de masa corporal (IMC), típo de EMC y farmacoterapia. Usando un inmunoensayo de electroquimioluminiscencia (ECLIA) y auto¬analizador (Cobas e 411), se analizaron los niveles séricos en ayunas de T total, encontrándose las siguientes particularidades: 1) Según la edad: disminución de -15 por ciento sobre los 80 años de edad (3.9±1.9 ng/ml) comparados con lo de 20-30 años (4.6±2.6 ng/ml) (p= -0.05). 2) De acuerdo al !MC: disminución de -22 por ciento en los pacientes con sobrepeso t!MC: 28, OM2 y DLP) y obesidad (!MC: 33): 3.9±IA y 3.9±1.5 ng/ml en relación al grupo control (!MC: 26) 5.0±2.1 ng/ml (p=-0.05), respectivamente. 3) En relación a las EMC: disminución de -22 por ciento versus el grupo control y, por subgrupos -26 por ciento en DLP, -22 por ciento en obesidad y -18 por ciento en DM2 (p=-0.05). 4) No se observó variación significativa en el subgrupo de fannacoterapia vs pacientes sin tratamiento, pero en quienes recibían hipolipemiantes disminuyó -15 por ciento (p=-0.05) (-17 por ciento SVT + EZT y -12 por ciento fibratos) y en quienes recibían hipoglucemiantes aumentó +19 por ciento (p=-0.05) (+23 por ciento hipoglicemiantes orales y +21 por ciento insulina, p=ns). 5) La frecuencia de hipogonadismo bioquímico fue de 10 por ciento, 26 por ciento y 42 por ciento, según los criterios internacionales de valores séricos mínimos de T total (-2.2ng/ml) y de los obtenidos intraensayo: -2.9ng/ml (-2.IOE) para el grupo control y -3.5 ng/ml (-1.5DE) para el grupo de EMC, respectivamente; destacandose una mayor frecuencia en el subgrupo de DLP para los tres niveles de corte...

High-resolution steady state magnetic resonance angiography of the carotid arteries: are intravascular agents necessary?: feasibility and preliminary experience with gadobenate dimeglumine.

PURPOSE: To prospectively evaluate the potential of gadobenate dimeglumine for high-resolution steady-state (SS) contrast-enhanced magnetic resonance angiography (CE-MRA) of the carotid arteries as an adjunct to conventional first-pass (FP) MRA, with computed tomography angiography (CTA) and digital subtraction angiography (DSA) as reference. MATERIALS AND METHODS: Institutional ethics committee approval and written informed consent were obtained. Forty consecutive patients underwent conventional FP MRA with 15 mL gadobenate dimeglumine, using a conventional 3D FLASH sequence (14 sec acquisition time). Immediately afterward, SS images were obtained using a high resolution coronal 3D FLASH sequence (240 sec acquisition time). All patients also underwent CTA and conventional DSA within 8 +/- 3 days. Three experienced radiologists assessed FP and SS image quality and calculated sensitivity, specificity, accuracy, and predictive values for stenosis grade and length, plaque morphology, and tandem lesions using DSA as reference. Detected stenoses were quantified and compared (Spearman rank correlation coefficient, [R(s)]; McNemar test) with DSA and CTA findings. Inter-read variability was assessed using kappa (kappa) statistics. The impact of SS acquisitions on diagnostic confidence and patient management was assessed. RESULTS: MRA FP and SS image quality was excellent in 63 (78.8%) and 46 (57.5%) vessels, adequate in 11 (13.8%) and 20 (25.0%) vessels, and poor in 6 (7.5%) and 14 (17.5%) vessels, respectively. Area under the curve analysis revealed no significant differences between MRA FP, MRA FP + SS, and CTA for the grading of stenoses (P = 0.838; accuracy values of 97.4%, 97.4%, and 98.7%, respectively). Greater accuracy (P < 0.001) was noted for FP + SS images over FP images alone for the assessment of plaque morphology (96.1% for FP + SS images vs. 83.3% for FP). Increased diagnostic confidence was noted for 49 (61.3%) vessels because of additional SS images whereas an impact on final diagnosis was noted in 8 (10%) cases. Good correlation was noted between SS image quality and impact on final diagnosis (R(s) = 0.7; P < 0.0001). CONCLUSION: SS imaging of the carotid arteries is feasible with gadobenate dimeglumine. The increased spatial resolution attainable allows improved evaluation of stenoses and plaque irregularity, yielding comparable diagnostic performance to that of CTA and DSA.

Factores de aterogenicidad y angiopatía en la diabetes mellitus tipo 2 de región andina

En la diabetes mellitus (DM) tipo 2 múltiples factores de riesgo general (ej. sexo, obesidad, dislipidemia, nefropatía progresiva, etc) son determinantes de la acelerada y severa aterosclerosis, con elevada morbilidad y prematura mortalidad. Estos factores fueron evaluados protocolizados transversalmente en 5 años a 258 pacientes con DM tipo 2 de la región andina (Quito 2815 m/snm).