Mapping the cerebral monoamine oxidase type A: positron emission tomography characterization of the reversible selective inhibitor [11C]befloxatone

Befloxatone is a competitive and reversible inhibitor of monoamine oxidase-A (MAOI-A). The aim of the study was to characterize the in vivo properties of [(11)C]befloxatone and to validate its use as a ligand for the study of MAO-A by positron emission tomography (PET). PET studies were performed in baboons after i.v. injection of [(11)C]befloxatone (551 +/- 70 MBq, i.e.14.9 +/- 1.9 mCi). [(11)C]Befloxatone enters rapidly in the brain with a maximum uptake at 30 min. Brain concentration of the tracer is high in thalamus, striatum, pons and cortical structures (1.5-1.8% of injected dose per 100 ml of tissue), and lower in cerebellum (1.07% injected dose/100 ml). Nonsaturable uptake, obtained after a pretreatment with a high dose of nonlabeled befloxatone (0.4 mg/kg), is very low and represents only 3% of the total uptake. Brain uptake of [(11)C]befloxatone is not altered by a pretreatment of a high dose with lazabemide (0.5 mg/kg i.v.), a selective MAOI-B but is completely blocked by a pretreatment with moclobemide (MAOI-A; 10 mg/kg). This confirms, in vivo, the selectivity of befloxatone for type A MAO. [(11)C]Befloxatone brain radioactivity was displaced by administration of unlabeled befloxatone (30 min after the tracer injection). The displacement of the tracer from its binding sites is dose-dependent, with an ID(50) of 0.02 mg/kg for all studied structures. These results indicate that [(11)C]befloxatone will be an excellent probe for the study of MAO-A in humans using PET.     

Myasthenia gravis Opportunistische Zytomegalievirus-Infektion nach langzeitiger Azathioprin-Therapie

Opportunistic infections after long-term treatment with azathioprine (AZA) have not been noted in patients with myasthenia gravis (MG). We report on a 56-year-old woman with generalized MG who presented with cytomegalovirus infection after being treated with AZA for 17 years. The indication for immunosuppressive treatment in MG should be regularly reconfirmed, particularly since at least 50% of patients can discontinue AZA after two to four years without risk of exacerbation.     

Can cardiac surgery cause hypopituitarism?

Apoplexy of pituitary adenomas with subsequent hypopituitarism is a rare but well recognized complication following cardiac surgery. The nature of cardiac on-pump surgery provides a risk of damage to the pituitary because the vascular supply of the pituitary is not included in the cerebral autoregulation. Thus, pituitary tissue may exhibit an increased susceptibility to hypoperfusion, ischemia or intraoperative embolism. After on-pump procedures, patients often present with physical and psychosocial impairments which resemble symptoms of hypopituitarism. Therefore, we analyzed whether on-pump cardiac surgery may cause pituitary dysfunction also in the absence of pre-existing pituitary disease. Twenty-five patients were examined 3–12 months after on-pump cardiac surgery. Basal hormone levels for all four anterior pituitary hormone axes were measured and a short synacthen test and a growth hormone releasing hormone plus arginine (GHRH-ARG)-test were performed. Quality of life (QoL), depression, subjective distress for a specific life event, sleep quality and fatigue were assessed by means of self-rating questionnaires. Hormonal alterations were only slight and no signs of anterior hypopituitarism were found except for an insufficient growth hormone rise in two overweight patients in the GHRH-ARG-test. Psychosocial impairment was pronounced, including symptoms of moderate to severe depression in 9, reduced mental QoL in 8, dysfunctional coping in 6 and pronounced sleep disturbances in 16 patients. Hormone levels did not correlate with psychosocial impairment. On-pump cardiac surgery did not cause relevant hypopituitarism in our sample of patients and does not serve to explain the psychosocial symptoms of these patients.     

In vivo quantification of myocardial dihydropyridine binding sites: a PET study in dogs.

Abnormalities in myocardial L-type Ca(2+) channel abundance and function have been described in cardiac hypertrophy and failure. In vivo quantification of the density of these channels using PET and an adequate ligand would provide new insights into cardiac disease. METHODS: The dihydropyridine L-type Ca(2+) channel antagonist S12968 (3-ethyl 5-methyl (-)-2-[(2-(2-aminoethoxy)ethoxy)methyl]-4-(2,3-dichlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate) was labeled with (11)C and injected in various amounts (5-23 nmol), 20 or 30 min apart, into dogs. This protocol allowed a separate evaluation of the density of binding sites (B(max)) as well as association and dissociation rate constants. The parameters were calculated using a nonlinear mathematic model. RESULTS: Using the multiinjection approach, a complete model describing interactions between S12968 and the dihydropyridine binding sites was obtained. B(max) was found to be 19.2 +/- 3.3 pmol x mL(-1) of tissue. Association and dissociation constants (estimated by K(on)/VR and K(d)VR, respectively) were found to be 0.015 +/- 0.01 mL x pmol(-1) x min(-1) and 4.2 +/- 2.2 nmol x mL(-1), respectively. CONCLUSION: The present data suggest that it is possible to measure myocardial dihydropyridine binding site density with a single radiosynthesis and a simple PET protocol that is not time consuming (75 min for the total examination, including transmission and emission scans). This methodology can be useful to investigate human cardiac disease in vivo.     

Presynaptic dopaminergic function in patients with restless legs syndrome: Are there common features with early Parkinson's disease?

The cause of restless legs syndrome (RLS) is unknown, but an involvement of the dopaminergic system and a possible relation to Parkinson's disease (PD) is suggested by the positive response to dopaminergic treatment. We imaged the striatal dopamine transporter with [(123)I] N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(chloro-phenyl) tropane ([(123)I]IPT) and single-photon emission computed tomography (SPECT) in 28 RLS patients, and compared the results with transporter binding in 29 patients with early PD and 23 age-matched controls. No difference in IPT binding was found between RLS patients and controls. IPT binding was correlated significantly with age in RLS patients and controls, whereas there was no relation with the duration of symptoms or severity of RLS. PD patients presented significant lower presynaptic IPT binding ipsi- and contralateral to the affected body side compared with RLS patients or controls. We found no common characteristics between RLS patients and patients with early PD detectable by dopamine transporter SPECT. Our results do not strengthen an identical pathophysiologic pathway between RLS and PD on the level of nigrostriatal presynaptic terminal function.     

Ga-66 labeled somatostatin analogue DOTA-DPhe1-Tyr3-octreotide as a potential agent for positron emission tomography imaging and receptor mediated internal radiotherapy of somatostatin receptor positive tumors

Radionuclide labeled somatostatin analogues selectively target somatostatin receptor (SSTR)-expressing tumors as a basis for diagnosis and treatment of these tumors. Recently, a DOTA-functionalized somatostatin analogue, DOTATOC (DOTA-DPhe1-Tyr3-octreotide) has been developed. This compound has been shown to be superior to the other somatostatin analogues as indicated by its uniquely high tumor-to-non-target tissue ratio. DOTATOC can be labeled with a variety of radiometals including gallium radioisotopes. Gallium-66 is a positron emitting radionuclide (T(1/2) =9.5 hr; beta+=56%), that can be produced in carrier free form by a low-beam energy cyclotron. In this study we investigated SSTR targeting characteristics of 66Ga-DOTATOC in AR42J rat pancreas tumor implanted nude mice as a potential agent for diagnosis and receptor-mediated internal radiotherapy of SSTR-expressing tumors. We compared our results with 67Ga- and 68Ga- labeled DOTATOC. The radiolabeling procedure gave labeling yield ranged from 85-95% and radiochemical and chemical purity was > 95%. In-vitro competitive binding curves and in-vivo competitive displacement studies with an excess of unlabeled peptide indicates that there is specific binding of the radioligand to SSTR. Animal biodistribution data and serial microPET images demonstrated rapid tumor uptake and rapid clearance from the blood and all tissues except kidney. Maximum % ID/g values for tumor were 10.0 +/- 0.7, 13.2 +/- 2.1 and 9.8 +/- 1.5 for 66Ga-, 67Ga-, and 68Ga-DOTATOC, respectively. Calculated tumor, kidney and bone marrow doses for 66Ga-DOTATOC based on biodistribution data were 178, 109 and 1.2 cGy/MBq, respectively.We conclude that 66Ga labeled DOTATOC can be used for PET diagnosis and quantitative imaging-based dosimetry of SSTR positive tumors. 66Ga-DOTATOC may also be used in higher doses for ablation of these tumors. However, kidney is the critical organ for toxicity (tumor/kidney ratio = 1.64), and high kidney uptake must be eliminated before devising a therapy protocol.