Radioimmunotherapy with alpha-particle emitting radionuclides.

An important consideration in the development of effective strategies for radioimmunotherapy is the nature of the radiation emitted by the radionuclide. Radionuclides decaying by the emission of alpha-particles offer the possibility of matching the cell specific reactivity of monoclonal antibodies with radiation with a range of only a few cell diameters. Furthermore, alpha-particles have important biological advantages compared with external beam radiation and beta-particles including a higher biological effectiveness, which is nearly independent of oxygen concentration, dose rate and cell cycle position. In this review, the clinical settings most likely to benefit from alpha-particle radioimmunotherapy will be discussed. The current status of preclinical and clinical research with antibodies labeled with 3 promising alpha-particle emitting radionuclides - (213)Bi, (225)Ac, and (211)At - also will be summarized.

Synthesis and pharmacological activity of a series of dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones, a novel class of potent cognition enhancers.

A series of dihydro-1H-pyrrolo[1,2-a]imidazole-2,5(3H,6H)-diones were synthesized. These bicylic derivatives contain both the 2-pyrrolidinone and 4-imidazolidinone nuclei, already recognized as important for cognition enhancing activity. In addition, these structures maintain the backbone of piracetam and oxiracetam with the acetamide side chain restricted in a folded conformation. Their ability to reverse scopolamine-induced amnesia was assessed in a one trial, step-through, passive avoidance paradigm. The main features observed are a potent antiamnestic activity after ip administration (minimal effective dose being between 0.3 and 1 mg/kg ip for most compounds), the presence of a bell-shaped dose-response curve and, generally, a reduction of biological activity after po administration. However, the unsubstituted compound (15, dimiracetam) shows no evidence of a bell-shaped dose-response curve and completely retains activity when given orally, being 10-30 times more potent than the reference drug oxiracetam.

Oxiracetam prevents the hippocampal cholinergic hypofunction induced by the NMDA receptor blocker AP7.

The intracerebroventricular injection of the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-7-phosphonoheptanoic acid (AP7) induces an increase of the hippocampal levels of acetylcholine (ACh) which is dose-dependent in the range 1.5-10 micrograms. Similar doses of AP7 failed to affect the ACh content of the striatum. The effect of the i.c.v. administration of 3.5 micrograms AP7 on hippocampal ACh levels was prevented by pretreatment with oxiracetam 100 mg/kg i.p. In the passive avoidance test the i.c.v. administration of 3.5 micrograms of AP7 caused severe amnesia which was antagonized in a dose-dependent manner by the pretreatment with oxiracetam. These results show that oxiracetam prevents the imbalance of cholinergic activity and the amnesia caused by blockade of NMDA receptors. The present study suggests that the hippocampal cholinergic activity is modulated by glutamatergic neuronal pathways and that the functional integrity of both systems is essential for learning and memory processes.

Oxiracetam antagonizes the disruptive effects of scopolamine on memory in the radial maze.

The effects exerted by oxiracetam on the disruption of performance induced by scopolamine in the radial arm maze were investigated in overtrained rats. Scopolamine induced a dose-related decrease in the efficiency of responding and an increase of running time. The effect of the SC injection of 0.2 mg/kg scopolamine on the efficiency of responding was antagonized by the IP administration of 30 mg/kg oxiracetam, while the effect on running time induced by the same dose of scopolamine was not. Physostigmine (0.3 mg/kg SC) antagonized both effects of 0.2 mg/kg scopolamine. Methylscopolamine, at the dose of 0.2 mg/kg SC, was devoid of any effect on both parameters. Increasing the dose of methylscopolamine to 0.63 mg/kg did cause serious peripheral effects which eventually prevented some animals from completing the task. Similar peripheral effects were observed after administration of 0.63 mg/kg scopolamine. The effects of this dose of scopolamine on efficiency and running time were not antagonized by pretreatment with 100 mg/kg oxiracetam. Oxiracetam alone (30 or 100 mg/kg IP) did not modify the performance of previously trained rats. The present results suggest that oxiracetam selectively restores cholinergic mechanisms which are involved in learning and memory.

Brain entry and direct central pharmacological effects of the nootropic drug oxiracetam. Oxiracetam: brain entry and pharmacological effects.

Oxiracetam administered systemically to rats as a 14C radiolabelled drug (200 mg/kg p.o. or 100 mg/kg intra-artery) enters the brain and is found unmetabolized above all in some of the brain areas functionally involved in the modulation of cognitive processes. Among the brain areas examined, the largest amount of compound was recovered in septum, followed by hippocampus; a smaller amount was found in cerebral cortex and striatum. 14C oxiracetam administered directly into the lateral ventricles of the brain presented a similar pattern of distribution, indicating that the tropism of the drug for the above brain areas does not depend on its route of administration. The amounts of oxiracetam that could reach the brain after systemically administered pharmacologically active doses were also estimated. These amounts (1.9 to 19 nmols/rat) were delivered through a permanently implanted cannula, into the lateral ventricles of the brains of conscious, freely moving rats. In this experimental condition oxiracetam dose-dependently antagonized the amnesia induced by scopolamine (0.66 mg/kg s.c.). The above findings clearly indicate that oxiracetam enters the brain and directly exerts its pharmacological activity there.

[3H]imipramine displacement and 5HT uptake inhibition by tryptoline derivatives: in rat brain 5-methoxytryptoline is not the autacoid for [3H]imipramine recognition sites.

A putative endacoid capable of displacing [3H]imipramine from its high affinity binding site and of inhibiting [3H]serotonin (5HT) uptake has been partially purified from rat brain tissue. It appears to be unevenly distributed in various rat brain structures following a pattern that only partially matches the extent of the serotonergic innervation in the rat brain structures investigated. The highest amounts have been recovered in striatum followed by hippocampus, cerebral cortex, brain stem and less in diencephalon, cerebellum, hypothalamus, olfactory bulb. Virtually no inhibitory activity on [3H]imipramine binding or on [3H]5HT uptake in addition to 5HT has been found in rat pineal extracts. Its absence in the pineal and various chemicophysical properties discussed in this report suggest that the rat brain endacoid for the imipramine binding site is not 5-methoxytryptoline, a compound previous proposed as the candidate for the role of endogenous ligand of [3H]imipramine recognition site. Moreover, the study of a series of tryptoline derivatives indirectly supports these conclusions.

Abnormality of alpha 1-adrenergic receptors in the frontal cortex of epileptic rats.

We found that the binding of [3H]prazosin, a selective ligand for alpha 1-adrenergic recognition sites, is significantly lower in the frontal cortex of the genetically epilepsy-prone rats (GEPRs), as compared with normal Sprague-Dawley rats. Scatchard analysis reveals a decrease in the Bmax of [3H]prazosin binding with no change in the apparent KD, suggesting that there are fewer alpha 1-adrenergic recognition sites in the frontal cortex of the GEPR. This abnormality is associated with a reduced capacity of norepinephrine (NE) to stimulate [3H]inositol monophosphate ([3H]IP1) formation in frontal cortex slices prelabeled with [3H]inositol. No significant differences in [3H]prazosin binding as well as NE-stimulated [3H]IP1 formation have been observed in other brain regions including hippocampus, corpus striatum, and inferior colliculus. These results indicate that a deficit in the alpha 1-adrenergic receptor system in the frontal cortex may play a role in the seizure process in the GEPR.

dl-9a-Deoxy-9a-methylene-PGI2 (a stable prostacyclin derivative): preliminary pharmacological data.

Carboprostacyclin (dl-9a-deoxy-9a-methylene-PGI2), a new stable PGI2-analogue, has been studied in vitro and in vivo. This analogue relaxes bovine coronary artery (potency ratio to PGI2 = 0.17), inhibits human PRP aggregation induced by ADP (IC50 = 12.5 nM2), deaggregates platelet clumps in cat heparinized blood (ED50 = 10.4 microgram/kg) and raises cAMP content in human PRP, but is less potent than PGI2. It is less potent (about 30 times) than PGI2 in lowering blood pressure in anaesthetized rats, inhibits basal gastric secretion in the rat and is 8 and 6 times less potent than PGE2 in protecting rat gastric mucosa from the lesions induced by stress and ASA, respectively, and about half as potent as PGE2 in protecting intestinal mucosa from damage by indomethacin.