A1 adenosine receptor antagonists as ligands for positron emission tomography (PET) and single-photon emission tomography (SPET).

The high affinity of 8-cyclopentyl-1,3-dipropylxanthine (CPX) for the A1 adenosine receptor (A1AR) provides a good lead for developing radioligands suitable for positron emission tomography (PET) and single-photon emission tomography (SPET). This study tested the hypothesis that the kinds of chemical modifications made in the synthesis of CPX analogues containing carbon-11, fluorine-18, or radioiodine will not alter affinity for the A1AR. This report describes the synthesis and radioligand binding assays of unlabeled CPX analogues having methyl, 2-methoxyethyl, 2-fluoropropyl, or 3-fluoropropyl substituents, respectively, at either N-1 (13a-d) or N-3 (8a-d) or an (E)-3-iodoprop-2-en-1-yl substituent at N-3 (8f). Compounds 8d,f and 13b,d antagonized the binding of [3H]CPX to the A1AR of rat brain with affinities similar to those of CPX; compound 8c was twice as potent as CPX. Analogues 8a,b and 13a were less potent than CPX, but for each the Ki of antagonism was > or = 0.5 nM. Attempts to iodinate the 8-(4-hydroxyphenyl) analogue of CPX failed, probably because the xanthine substituent strongly deactivated the phenol toward electrophilic iodination. In summary, several of the modifications of the propyl groups of CPX needed to produce ligands for imaging by PET and SPET preserve or enhance affinity for the A1AR.

Binding of tritiated and radioiodinated ZM241,385 to brain A2A adenosine receptors.

Autoradiography on rat brain using tritiated (1*), mono- (2*) and di-radioiodinated (3*) derivatives of the A(2A) adenosine receptor antagonist ZM241,385 showed high receptor density in striatum. K(D)s of 1*, 2* and 3* were 0.4, 2.2 and 15 nM and nonspecific binding was 5, 40 and 50% of total binding. Striatal uptake of 2* in mice was approximately 0.2% ID/g 60 min post-injection; blocking by 2 was insignificant. Poor penetration of the blood brain barrier and high nonspecific binding make 2* unsuitable for imaging striatal receptors.

PET-pharmacokinetics of 18F-octreotide: a comparison with 67Ga-DFO- and 86Y-DTPA-octreotide.

The quantitative uptake kinetics of (2-[18F]fluoropropionyl-(D)phe1)-octreotide (I), a somatostatin (SRIF) receptor-specific tracer, was measured by PET. Conventional organ biodistribution and in vivo stabilities of the tracer as well as in vivo displacement and SRIF receptor blocking were determined. The 18F-fluorinated octreotide was compared with ([67Ga]-DFO-B-succinyl-(D)phe1)-octreotide (II) and ([86Y]-DTPA-(D)phe1)-octreotide (III). Initially, 2-10 MBq of the labeled tracers were injected into male Lewis rats bearing an exocrine pancreatic islet cell tumor. PET measurements were performed dynamically between 0 and 120 min postinjection. Organ distributions were determined 5, 15, 30, 60, and 120 min postinjection. The extent of metabolic degradation was analyzed in serial blood and urine samples as well as in homogenized samples of tumor, liver, and kidney. The uptake of (I) by the tumor was rapid (maximum accumulation at 1-2 min postinjection) and high (about 0.5 +/- 0.2% ID/g), followed by a fast and continuous release with koff = 10 +/- 2. 10(-5) s-1. The tracer was found to remain intact in vivo up to 120 min postinjection. Specific binding of (I) to SRIF receptors in the adrenals, the pancreas, and the pituitary gland was demonstrated in vivo by pretreatment and displacement experiments. Compound (II) also showed a fast uptake by the tumor. Its tumor residence half-life was longer (koff = 3.0 +/- 0.5 . 10(-5) s-1). Compound (II) was also predominantly excreted intact. One hour postinjection, the remaining activity in the blood pool was found to be bound to serum proteins. Early uptake kinetics for compound (III) were also rapid but reached only half the tumor uptake of (II). Compared to (I), the release of 86Y-activity from the tumor was slower (koff = 3.1 +/- 1.3 . 10(-5) s-1). Compared to (II), compound (III) was considerably less stable in vivo. The main critical organs for (II) and (III) are kidneys and bones, whereas (I) is predominantly accumulated in the liver. The in vivo behavior of (I) closely resembles 14C-labeled octreotide. Thus, 18F-labeled octreotide may be of interest in the quantitation and investigation of in vivo properties of somatostatin receptors by PET. However, the short residence of (2-[18F]fluoropropionyl-(D)phe1)-octreotide in tumors and its hepatobiliary excretion may complicate the interpretation of abdominal tumors.

Evaluation of radioiodinated 8-Cyclopentyl-3-[(E)-3-iodoprop-2-en-1-yl]-1-propylxanthine ([*I]CPIPX) as a new potential A1 adenosine receptor antagonist for SPECT.

8-Cyclopentyl-3-[(E)-3-[(131)I]iodoprop-2-en-1-yl]-1-propylxanthine (2*) was generated by iododestannylation of the tributyl-stannyl-precursor with [(131)I]NaI and chloramine T. The radiochemical yield of 2* was 82 +/- 4%, and the purity exceeded 98%. The specific activity was 33 +/- 19 GBq/micromol. Affinities for rat, pig and human A(1) adenosine receptors (A(1)ARs) were in the low nanomolar range, but poor selectivity for the human A(1)AR over the A(2A)AR was found. Additionally, in vitro and ex vivo autoradiographic studies revealed high unspecific binding which makes this ligand unsuitable for SPECT imaging.

Effect of Huntington's and Alzheimer's diseases on the transport of nicotinic acid or nicotinamide across the human blood-brain barrier.

The cerebral uptake of 11C-nicotinic acid (11C-NAC) and 11C-nicotinamide (11C-NAM) was quantified by the use of PET. Based on the amount of activity injected, the PET images showed a low cerebral uptake of 11C-NAC, while 11C-NAM was clearly visualized in the cortical areas. This discrepancy was found to be the result of the binding of 11C-NAC to the red blood cells by a factor of 5 to 20 above that for 11C-NAM. 11C-NAM was better extracted by the cerebrum than 11C-NAC, as shown by the mean values of the cortical tissue/plasma ratio of 1.9 for 11C-NAC and 5 for 11C-NAM at 30 min. post-injection. An analysis of Patlak-Gjedde plot curves revealed a metabolic compartment for 11C-NAC and 11C-NAM with similar values of about 0.02 l/min for the accumulation constant K3. This was indicative of a slower transport rate for 11C-NAC. A significant finding of the study was the increasing ratio of activity concentrations in red blood cells versus the concentrations in plasma (over time). There were no significant differences between the data from normal volunteers and patients with Huntington's or Alzheimer's disease.

[Acute psychogenic strabismus in psychosomatic disorders (author's transl)]. / Psychogenes Schielen im Rahmen psychoorganischer Erkrankungen.

Two cases of convergent strabismus with acute onset are described. One case was caused by a psychogenic disorder, the other by a basilar meningitis.

75,77Br- and 123I-analogues of D-glucose as potential tracers for glucose utilisation in heart and brain.

A number of D-glucose analogues labelled with either the positron emitter 75Br (T 1/2 = 1.6 h) or the single photon emitter 123I (T 1/2 = 13.3 h) were studied as potential tracers for glucose utilisation in heart and brain. Of these, 3-deoxy-3-bromo-D-glucose, 3-deoxy-3-iodo-D-glucose, methyl 2-deoxy-2-bromo-beta-D-glucoside and methyl 2-deoxy-2-iodo-beta-D-glucoside showed little uptake of radioactivity into brain and an unfavourable ratio of heart-to-blood and heart-to-lung concentrations. In contrast, methyl 3,4,6-tri-O-acetyl-2-deoxy-2-iodo-beta-D-glucoside (MTIG) and methyl 3,4,6-tri-O-acetyl-2-deoxy-2-bromo-beta-D-glucoside (MTBG) showed promising brain uptake (160% MBC for MTBG) with a good brain-to-blood concentration ratio of 0.8. MTBG is not metabolically altered in the brain. Thus, this compound may be a promising tracer for measuring glucose transport if it proves to be a substrate for the hexose carrier at the blood-brain-barrier.

[Electroophthalmological investigations in amblyopia (author's transl)]. / Elektroophthalmologische Untersuchungen bei Amblyopie.

In the case of 8 amblyopic patients the ERG and the brightness VECP, as well as the TV-pattern reversal VECPs in whole field and upper and lower half field stimulation, were traced. In the ERG (a- and b-wave) and the brightness VECP significant differences were established neither in the amplitude nor in the latenz between amblyopic and healthy eyes. The amplitude of the pattern reversal VECPs in whole field and lower half field stimulation was significantly reduced in all 8 patients on the side of the amblyopic eye.

[Follow-up study in patients with neuritis retrobulbaris (author's transl)]. / Verlaufsbeobachtungen der Neuritis retrobulbaris -- Vergleichende psychophysische und elektroophthalmologische Befunde.

In 11 patients with multiple sclerosis (MS) and eight patients in whom MS was not verified visus, computerized perimetry, bipolar flash evoked cortical potential (H-EP) and pattern-reversal evoked cortical response (M-EP) were recorded in the acute stage and convalescent period of neuritis retrobulbaris. In the acute stage visual field deficiencies, diminutions of H-EP and M-EP amplitudes and increases in H-EP latencies were seen in both eyes in all cases. The most severe pathologic changes were found in the worst eyes in the group without MS. In the convalescent period a complete restitution of the electro-ophthalmological parameters was found in neither group of patients by statistical methods. Restitution was more common in patients who were not suffering from MS.

[Differential diagnosis of amblyopia and retrobulbar neuritis with electroophthalmologic methods]. / Differentialdiagnose der Amblyopie und der retrobulbären Neuritis durch elektroophthalmologische Methoden.

The electroretinogram (ERG), the brightness visual evoked cortical potential (H-EP) and the pattern reversal visual evoked cortical potential (M-EP) were recorded from 7 patients with amblyopia and 5 patients with neuritis retrobulbaris. The ERGs and the H-EPs of the amblyopic eyes were normal whereas the amplitude of the M-EP was significant diminished. The parameters of the ERG recorded from the patients with neuritis retrobulbaris showed normal values, however the H-EPs were significantly decreased and the peaktimes were delayed. Also a decrease in the amplitudes of the M-EPs was noticed. This method is a usefull clinical contribution in the differential diagnosis between amblyopia and neuritis retrobulbaris.

[Regression of a Kayser-Fleischer ring in a case of Wilson's disease during penicillamine therapy (author's transl)]. / Die Rückbildung eines Kayser-Fleischer-Ringes bei Morbus Wilson unter Penicillamintherapie.

The disappearance of a Kayser-Fleischer ring induced by the administration of penicillamine (D-penicillamine) for 17 years is described. The ring disappeared only in the lateral and medial portions leaving superior and inferior crescents. Possible mechanisms of this partial regression of the ring ae discussed.

[Clinical experience in treatment of glaucoma with timolol (author's transl)]. / Klinische Erfahrungen bei der Glaukombehandlung mit Timolol.

Forty patients with primary and secondary glaucoma were treated with the beta-blocking agent Timolol for six months. We used a 0.25% or 0.5% solution twice a day. In several cases sufficient pressure regulation was achieved by means of Timolol monotherapy. If pilocarpine or acetazolamide therapy was not sufficient we used a combination therapy with Timolol.

[Frontotransversal gunshot through both orbits leading to destruction of the bulbs in a case of attempted suicide (author's transl)]. / Frontotransversaler Durchaschuss beider Orbitase mit beidseitiger Bulbusberstung bei Suizidversuch.

In a case of attempted suicide a frontotransversal gunshot through both orbits led to symmetrical destruction of the bulbs and orbits. Examination revealed a rupture of both bulbs, fractures of the orbital roofs and floors, and destruction of the os ethmoidale. In the frontal cortex we found focal contusions. The physical effect of the gunshot on one hand, and the special anatomical relations of the orbit on the other, explain the serious consequences of orbital gunshot damages.

[A live intraocular parasite (author's transl)]. / Lebender intraokularer Parasit.

Using the first film documentation of such a case, the differential diagnostic and therapeutic difficulties in a case of live intravitreal Filaria are discussed. The visual acuity of the affected eye was unimpaired. The parasite was destroyed by systemic anthelmintic therapy. The only functional damage to the eye was that the visual field was concentrically reduced to approximately 40 degrees.

[Qualitative rapid screening of glaucoma outpatients with the octopus computer perimeter (author's transl)]. / Qualitatives Glaukomkurzprogramm des Computerperimeters Octopus in der Glaukomambulanz.

The results of examinations of 60 outpatients with suspected glaucoma show that the qualitative program with fast screening of the 30-degree field enables a prompt decision to be made as to whether the visual fields of such patients are normal or pathologic.

[Partial canaliculus transplantation (author's transl)]. / Die partielle Canaliculustransplantation.

In some cases of palpebral tumors, causing epiphora by canalicular obstruction, surgical reconstruction of the lacrimal system is necessary . The defect of the nasal part of the lower lid is closed by transplantation of the nasal part of the upper lid of the other eye, including a part of the canaliculus. Three patients suffering from basaliomas in the region of the lower canaliculus were treated by this method. Good cosmetic and functional results were achieved.

[Rehabilitation after serious perforating eye injuries (author's transl)]. / Zur Rehabilitation nach schweren perforierenden Augenverletzungen.

In a recent study of perforating eye injuries the authors found that in 21% there was no binocular function. To prevent complications arising from this, early fitting of hard contact lenses seems necessary. The problems of fitting contact lenses to posttraumatically aphakic eyes are discussed, with special regard to aniseikonia.

[Diagnosis and differential diagnosis of hysteric amblyopia using psychophysical and electro-ophthalmological examination methods (author's transl)]. / Diagnose und Differentialdiagnose der hysterischen Amblyopie mit psychophysischen und elektroophthalmologischen Untersuchungsmethoden.

In three patients with psychogenic amblyopia the computerized visual field, the ERG, the flash light (H-EP) and pattern reversal stimulated (M-EP) cortical potentials were recorded. Differential diagnosis between psychogenic amblyopia on the one hand, and functional amblyopia and organic lesions of the retrobulbar visual pathways on the other was shown to be possible. In the cases with organic retrobulbar lesions of visual pathways, visual field defects and pathologic H-EP's and M-EP's were found. In functional amblyopia only the M-EP responses are diminished in amplitude. In psychogenic amblyopia only the computerized visual field shows pathologic changes.

[The action of ethylenediaminetetraacetate on the retina. Electronmicroscopic study (author's transl)]. / Die Wirkung von Athylendiamintetraessigsäure auf die Retina. Elektronenoptische Studie.

Electron microscopic investigations show that intravitreal application of EDTA causes destruction of the viteous body and damage in all layers of the retina. Therefore, it is concluded that it is useless to try prevention of metallosis of the eye by EDTA.