Water-soluble mmp-9 inhibitor prodrug generates active metabolites that cross the blood-brain barrier.

MMP-9 plays a detrimental role in the pathology of several neurological diseases and, thus, represents an important target for intervention. The water-soluble prodrug ND-478 is hydrolyzed to the active MMP-9 inhibitor ND-322, which in turn is N-acetylated to the even more potent metabolite ND-364. We used a sensitive bioanalytical method based on ultraperformance liquid chromatography with multiple-reaction monitoring detection to measure levels of ND-478, ND-322, and ND-364 in plasma and brain after administration of ND-478 and the metabolites. ND-478 did not cross the blood-brain barrier, as was expected; however the active metabolites ND-322 and ND-364 distributed to the brain. The active compound after administration of either ND-478 or ND-322 is likely ND-364. ND-322 is N-acetylated in both brain and liver, but it is so metabolized preferentially in liver. Since N-acetyltransferases involved in the metabolism of ND-322 to ND-364 are polymorphic, direct administration of the N-acetylated ND-364 would achieve the requisite therapeutic levels in the brain.

Matrix metalloproteinase 9 targeting peptides: syntheses, 68Ga-labeling, and preliminary evaluation in a rat melanoma xenograft model.

Biopanning of tumor cells was used in order to identify matrix metalloproteinase 9 (MMP-9) targeting peptides. The tumor cell targeting peptide (TCTP-1) and two modified versions thereof were evaluated as imaging agents for positron emission tomography (PET) using a rat melanoma xenograft model. For the PET imaging purposes, the 3 peptides were 1,4,7,10-tetraazacyclo-dodecane-N',N'',N''',N''''-tetraacetic acid (DOTA) conjugated and labeled with Gallium-68 ((68)Ga) and preliminarily evaluated: (1) cyclic (68)Ga-DOTA-TCTP-1 with cystine bridge, (2) cyclic (68)Ga-DOTA-lactam-TCTP-1 with a lactam bridge, and (3) linear (68)Ga-DOTA-lin-TCTP-1. The whole-body distribution kinetics and tumor targeting of the intravenously administered (68)Ga-DOTA-peptides were evaluated in vivo by PET and ex vivo by measuring the radioactivity of excised tissues. In addition, the in vivo stability of the radiolabeled peptides in rat plasma, tumor tissue, and urine was studied. All (68)Ga-DOTA-peptides were cleared via the liver and kidneys, and approximately 44% of injected radioactivity was excreted in urine during 120 min after injection. Ex vivo biodistribution studies showed a tumor-to-muscle ratio of 5.5 ± 1.3 (mean ± SD) for (68)Ga-DOTA-TCTP-1, 3.2 ± 0.2 for (68)Ga-DOTA-lactam-TCTP-1, and 3.2 ± 0.6 for (68)Ga-DOTA-lin-TCTP-1 at 120 min after injection. The (68)Ga-DOTA-lactam-TCTP-1 peptide appeared to be the most stable in vivo. The fraction of intact (68)Ga-DOTA-lactam-TCTP-1 in tumor was 59 ± 4.2% at 120 min after injection. The stability was moderate for (68)Ga-DOTA-TCTP-1 and poor for (68)Ga-DOTA-lin-TCTP-1. The possibility of imaging tumors that overexpress MMP-9, such as melanoma, by using radiolabeled TCTP peptides in PET imaging makes these peptides highly attractive for diagnostic and therapeutic applications. However, further modifications to improve the stability and affinity of the peptides are needed.

Spinal matrix metalloproteinase-9 contributes to physical dependence on morphine in mice.

Preventing and reversing opioid dependence continues to be a clinical challenge and underlying mechanisms of opioid actions remain elusive. We report that matrix metalloproteinase-9 (MMP-9) in the spinal cord contributes to development of physical dependence on morphine. Chronic morphine exposure and naloxone-precipitated withdrawal increase activity of spinal MMP-9. Spinal inhibition or targeted mutation of MMP-9 suppresses behavioral signs of morphine withdrawal and the associated neurochemical alterations. The increased MMP-9 activity is mainly distributed in the superficial dorsal horn and colocalized primarily with neurons and small numbers of astrocytes and microglia. Morphine exposure and withdrawal increase phosphorylation of NR1 and NR2B receptors, ERK1/2, calmodulin-dependent kinase II, and cAMP response element binding proteins; and such phosphorylation is suppressed by either spinal inhibition or targeted mutation of MMP-9. Further, spinal administration of exogenous MMP-9 induces morphine withdrawal-like behavioral signs and mechanical allodynia, activates NR1 and NR2 receptors, and downregulates integrin-beta1, while a function-neutralizing antibody against integrin-beta1 suppresses MMP-9-induced phosphorylation of NR1 and NR2B. Morphine withdrawal-induced MMP-9 activity is also reduced by an nNOS inhibitor. Thus, we hypothesize that spinal MMP-9 may contribute to the development of morphine dependence primarily through neuronal activation and interaction with NR1 and NR2B receptors via integrin-beta1 and NO pathways. The other gelatinase, MMP-2, is not involved in morphine dependence. Inhibiting spinal MMP-9 or MMP-2 reduces chronic and/or acute morphine tolerance. This study suggests a novel therapeutic approach for preventing, minimizing, or reversing opioid dependence and tolerance.

Cinética de la metaloproteasa 9: importancia del ritmo luz-oscuridad de la metaloproteasa 9 en el síndrome coronario agudo / The kinetics of metalloproteinase-9: the significance of the light-dark cycle in metalloproteinase-9 in acute coronary syndrome

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Cinética de la metaloproteasa 9: importancia del ritmo luz-oscuridad de la metaloproteasa 9 en el síndrome coronario agudo. Respuesta / The kinetics of metalloproteinase-9: the significance of the light-dark cycle in metalloproteinase-9 in acute coronary syndrome. Response

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