In vitro
 and ex vivo
 effects of a selective nociceptin/orphanin FQ (N/OFQ) peptide receptor antagonist, CompB, on specific binding of [3
H]N/OFQ and [35
S]GTPγ
S in rat brain and spinal cord

Summary Aim: Disturbances of the D4 receptor subtype have been implicated in the genesis of a broad range of psychiatric disorders. In order to assess the suitability of a radioiodinated analogue of the D4-selective ligand FAUC 113 for tracer studies in vivo, we investigated the in-vivo stability, biodistribution and brain-uptake of 7-131I-FAUC 113 in Sprague-Dawley rats. Methods: Radiolabelling was carried out with high radiochemical yield and specific activity. After intravenous injection, blood and tissue samples, taken at designated time intervals, were collected for analysis. Analyses of metabolites were performed by radiohplc and radio-tlc. For in-vivo evaluation, sagittal cryo-sections of the rat brain were investigated by in-vitro and exvivo autoradiography on a μ-Imager system. Results: 7-131I-FAUC 113 was rapidly cleared from blood. Highest uptake was observed in kidney (0.603±0.047% ID/g, n=4) and liver (0.357±0.070% ID/g, n=4) at 10 min p.i.; 7-131I-FAUC 113 displayed rapid uptake (0.21-0.26% ID/g) and fast clearance in various brain regions consistent with the determined logP-value of 2.36±0.15 (n=4). In-vivo stability of 7-131I-FAUC 113 was confirmed in the frontal cortex (>95%). Ex-vivo autoradiography revealed a frontal cortex-to-cerebellum ratio of 1.57±0.13 at 10 min p.i. (n=6). Coinjection with L-750667 could not suppress any putative specific binding of 7-131I-FAUC 113. In-vitro autoradiography using authentic 7-iodo-FAUC 113 or L-750667 failed to cause significant displacement of the radioligand. Conclusions: Radioiodinated FAUC 113 does not allow imaging of D4 receptors in the rat brain in vivo nor in vitro. Further work should aim at the development of selective dopamine D4 radioligands with improved tracer characteristics, such as receptor affinity and subtype selectivity, specific activity or blood-brainbarrier permeability.

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PSMA-D4 Radioligand for Targeted Therapy of Prostate Cancer: Synthesis, Characteristics and Preliminary Assessment of Biological Properties

International Journal of Molecular Sciences ◽

10.3390/ijms22052731 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2731

Author(s):

Piotr Garnuszek ◽

Urszula Karczmarczyk ◽

Michał Maurin ◽

Arkadiusz Sikora ◽

Jolanta Zaborniak ◽

...

Keyword(s):

Prostate Cancer ◽

Targeted Therapy ◽

Ex Vivo ◽

Specific Binding ◽

Biological Evaluation ◽

In Vitro Assays ◽

The Novel ◽

Distribution Profile ◽

System L

A new PSMA ligand (PSMA-D4) containing the Glu-CO-Lys pharmacophore connected with a new linker system (L-Trp-4-Amc) and chelator DOTA was developed for radiolabeling with therapeutic radionuclides. Herein we describe the synthesis, radiolabeling, and preliminary biological evaluation of the novel PSMA-D4 ligand. Synthesized PSMA-D4 was characterized using TOF-ESI-MS, NMR, and HPLC methods. The novel compound was subject to molecular modeling with GCP-II to compare its binding mode to analogous reference compounds. The radiolabeling efficiency of PSMA-D4 with 177Lu, 90Y, 47Sc, and 225Ac was chromatographically tested. In vitro studies were carried out in PSMA-positive LNCaP tumor cells membranes. The ex vivo tissue distribution profile of the radioligands and Cerenkov luminescence imaging (CLI) was studied in LNCaP tumor-bearing mice. PSMA-D4 was synthesized in 24% yield and purity >97%. The radio complexes were obtained with high yields (>97%) and molar activity ranging from 0.11 to 17.2 GBq mcmol−1, depending on the radionuclide. In vitro assays confirmed high specific binding and affinity for all radiocomplexes. Biodistribution and imaging studies revealed high accumulation in LNCaP tumor xenografts and rapid clearance of radiocomplexes from blood and non-target tissues. These render PSMA-D4 a promising ligand for targeted therapy of prostate cancer (PCa) metastases.

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THE PATHOLOGIC EFFECTS OF STREPTOCOCCI FROM CASES OF POLIOMYELITIS AND OTHER SOURCES

Journal of Experimental Medicine ◽

10.1084/jem.25.4.557 ◽

1917 ◽

Vol 25 (4) ◽

pp. 557-580 ◽

Cited By ~ 25

Author(s):

Carroll G. Bull

Keyword(s):

Spinal Cord ◽

Guinea Pigs ◽

The Other ◽

Laboratory Animals ◽

Histological Changes ◽

Other Hand ◽

Brain And Spinal Cord ◽

The Brain

Streptococci cultivated from the tonsils of thirty-two cases of poliomyelitis were used to inoculate various laboratory animals. In no case was a condition induced resembling poliomyelitis clinically or pathologically in guinea pigs, dogs, cats, rabbits, or monkeys. On the other hand, a considerable percentage of the rabbits and a smaller percentage of some of the other animals developed lesions due to streptococci. These lesions consisted of meningitis, meningo-encephalitis, abscess of the brain, arthritis, tenosynovitis, myositis, abscess of the kidney, endocarditis, pericarditis, and neuritis. No distinction in the character or frequency of the lesions could be determined between the streptococci derived from poliomyelitic patients and from other sources. Streptococci isolated from the poliomyelitic brain and spinal cord of monkeys which succumbed to inoculation with the filtered virus failed to induce in monkeys any paralysis or the characteristic histological changes of poliomyelitis. These streptococci are regarded as secondary bacterial invaders of the nervous organs. Monkeys which have recovered from infection with streptococci derived from cases of poliomyelitis are not protected from infection with the filtered virus, and their blood does not neutralize the filtered virus in vitro. We have failed to detect any etiologic or pathologic relationship between streptococci and epidemic poliomyelitis in man or true experimental poliomyelitis in the monkey.

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