Iodinated PK 11195 as an ex vivo marker of neuronal injury in the lesioned rat brain

Chalon, Sylvie; Pellevoisin, Christian; Bodard, Sylvie; Vilar, Marie-Paule; Besnard, Jean‐Claude; Guilloteau, Denis

doi:10.1002/(sici)1098-2396(199612)24:4<334::aid-syn3>3.0.co;2-e

Cited by 9 publications

(3 citation statements)

References 19 publications

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“…Injections of the excitotoxin, quinolinic acid (QA; Sigma‐Aldrich, Poole, UK), were stereotaxically placed in the dorsal region of the right striatum at two loci (coordinates: 8.0 mm anterior to bregma; 2.4 mm lateral to the midline; and 3.5 and 5.0 mm ventral to the pial surface) using a Hamilton syringe. Each rat received a total of 120 nmol of QA in 1 µL of phosphate‐buffered saline (PBS; 0.01 m phosphate, pH 7.4) over a 10‐min period (Chalon et al ., 1996; Nakao et al ., 1996; Nicholson et al ., 1996). The cannula was then left in position for a further 5 min before being slowly removed.…”

Section: Methodsmentioning

confidence: 99%

Synaptic localization of GABA_A receptor subunits in the substantia nigra of the rat: effects of quinolinic acid lesions of the striatum

Fujiyama¹,

Stephenson

Bolam³

2002

Eur J of Neuroscience

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The inhibitory amino acid, gamma-aminobutyric acid (GABA), plays a critical role in the substantia nigra (SN) in health and disease. GABA transmission is controlled in part by the type(s) of GABA receptor expressed, their subunit composition and their location in relation to GABA release sites. In order to define the subcellular localization of GABA(A) receptors in the SN in normal and pathological conditions, sections of SN from control rats and rats that had received quinolinic acid lesions of the striatum were immunolabelled using the postembedding immunogold technique with antibodies against subunits of the GABA(A) receptor. Immunolabelling for alpha1, beta2/3 and gamma2 subunits was primarily located at symmetrical synapses. Double-labelling revealed that beta2/3 subunit-positive synapses were formed by terminals that were enriched in GABA. Colocalization of alpha1, beta2/3 and gamma2 subunits occurred at individual symmetrical synapses, some of which were identified as degenerating terminals derived from the striatum. In the SN ipsilateral to the striatal lesion there was a significant elevation of immunolabelling for beta2/3 subunits of the GABA(A) receptor at symmetrical synapses, but not of GluR2/3 subunits of the AMPA receptor at asymmetrical synapses. It was concluded that fast GABA(A)-mediated transmission occurs primarily at symmetrical synapses within the SN, that different receptor subunits coexist at individual synapses and that the upregulation of GABA(A) receptors following striatal lesions is expressed as increased receptor density at synapses. The upregulation of GABA(A) receptors in Huntington's disease and its models is thus likely to lead to an increased efficiency of transmission at intact GABAergic synapses in the SN and may partly underlie the motor abnormalities of this disorder.

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Section: Methodsmentioning

confidence: 99%

Synaptic localization of GABA_A receptor subunits in the substantia nigra of the rat: effects of quinolinic acid lesions of the striatum

Fujiyama¹,

Stephenson

Bolam³

2002

Eur J of Neuroscience

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“…In contrast, 124 I-PK 11195's longer half-life (4.2 days) enables us to image tumors. Although there are some publications that report using ligands of TSPO to image brain, for example, Chalon et al 30 reported use of iodinated PK 11195 as an ex vivo marker of neuronal injury in the lesioned rat brain, we are the first to use 124 I-PK 11195 as the imaging agent for cancers here. In our approach to develop a bifunctional agent for both tumor imaging and phototherapy, we are interested in conjugating I-PK 11195 with photosensitizers.…”

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confidence: 95%

TSPO 18 kDa (PBR) Targeted Photosensitizers for Cancer Imaging (PET) and PDT

Chen

Sajjad

Wang

et al. 2010

ACS Med. Chem. Lett.

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Translocator protein (TSPO) 18 kDa overexpression has been observed in a large variety of human cancers, especially breast cancers. PK 11195, an isoquinoline analogue, is one of the ligands of highest TSPO binding affinity. Due to the long biological half life of our photosensitizers, there is a need to label them with a long lived radioisotope, for example I-124. Our objectives are to find translocator protein targeted photosensitizers for both tumor imaging (PET) and photodynamic therapy (PDT). I-PK 11195 is conjugated with the tumor avid photosensitizer HPPH. We find that those two tumor avid components complement each other and make the conjugate molecule even more tumor avid; compared to the photosensitizer itself, the conjugate is found to show improved PDTefficacy. It is concluded that I-PK 11195 can be a good vehicle to deliver radionuclide and photosensitizer to TSPO overexpressed tumor regions. Such conjugates could be useful for both tumor imaging (PET) and PDT.KEYWORDS Photodynamic therapy (PDT), translocator protein (TSPO), peripheral benzodiazepine receptor (PBR), positron emission tomography (PET), PK 11195, cancer target specific P BR (peripheral benzodiazepine receptor) is suggested to be named Translocator Protein (18 kDa) (TSPO 18 kDa) by Papadopoulos et al.1 based on its structure and molecular function. TSPO is involved in numerous functions, [2][3][4] including the role in steroidogenesis and mitochondrial respiration 5,6 and apoptosis regulation. 7-9 A number of findings argue in favor of the development of TSPO targeting approaches in the treatment of human cancers. (i) TSPO overexpression has been observed in a large variety of human cancers, 10 especially in breast cancers.11 (ii) TSPO is a component of the central regulatory complex of apoptosis; 12 this suggests that TSPO targeting could be of interest in combination with various antitumor therapies. (iii) TSPO binding by high-affinity ligands enhances apoptosis induction of numerous inducers; moreover, TSPO ligands are able to reverse the Bcl-2 cytoprotective effect. 13For breast cancers, it was reported 11 that TSPO expression and TSPO-mediated cholesterol transport are involved in cell proliferation and aggressive phenotype expression, thus participating in the advancement of the disease. Altogether, these observations justify the use of TSPO ligands in combination with other antitumor therapies for the diagnosis and treatment of breast cancers. Although a number of wide varieties of endogenous and synthetic molecules were reported to have high affinities for TSPO, 14 currently PK 11195 is still the most widely used TSPO ligand and regarded as the gold standard.

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“…Radiolabelled analogues of these compounds, particularly 11 C and 123 I labelled PK 11 195 have subsequently been used to map PBR receptors in the human heart and brain as well as imaging tumours and neurological disorders in vivo [22][23][24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of [¹²³I]iodine labelled imidazo[1,2-b] pyridazines as potential probes for the study of peripheral benzodiazepine receptors using SPECT

Katsifis¹,

Barlin²,

Mattner³

et al. 2004

Radiochimica Acta

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The pyridazines 3-acetamidomethyl-6-chloro-2-(4 -iodophenyl)imidazo[1,2-b]pyridazine 1 (IC 50 = 1.6 nM) and 3-benzamidomethyl-6-iodo-2-(4 -t-butylphenyl)imidazo[1,2-b] pyridazine 2 (IC 50 = 4.2 nM), are high affinity and selective ligands for the Peripheral Benzodiazepine Receptors (PBR) compared to the Central Benzodiazepine counterparts. The [ 123 I]1 and [ 123 I]2 labelled analogues of these compounds were subsequently synthesised for the potential study of the PBR in vivo using SPECT. Radioiodination of [ 123 I]1 was achieved by iododestannylation of the corresponding tributyl tin precursor with Na[ 123 I] in the presence of peracetic acid or chloramine-T and the product isolated by C-18 RP HPLC. Radioiodination of [ 123 I]2 was achieved by copper assisted bromine [ 123 I]iodine exchange of the corresponding bromo precursor in the presence of acetic acid and sodium bisulfate as reducing agent at 200 • C. Purification of the crude products were achieved by semi-preparative C-18 RP HPLC to give the products in radiochemical yields > 90%. The products were obtained in > 97% chemical and radiochemical purity and with specific activities > 180 GBq/µmol.

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Iodinated PK 11195 as an ex vivo marker of neuronal injury in the lesioned rat brain

Cited by 9 publications

References 19 publications

Synaptic localization of GABA_A receptor subunits in the substantia nigra of the rat: effects of quinolinic acid lesions of the striatum

Synaptic localization of GABA_A receptor subunits in the substantia nigra of the rat: effects of quinolinic acid lesions of the striatum

TSPO 18 kDa (PBR) Targeted Photosensitizers for Cancer Imaging (PET) and PDT

Synthesis of [¹²³I]iodine labelled imidazo[1,2-b] pyridazines as potential probes for the study of peripheral benzodiazepine receptors using SPECT

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Iodinated PK 11195 as an ex vivo marker of neuronal injury in the lesioned rat brain

Cited by 9 publications

References 19 publications

Synaptic localization of GABAA receptor subunits in the substantia nigra of the rat: effects of quinolinic acid lesions of the striatum

Synaptic localization of GABAA receptor subunits in the substantia nigra of the rat: effects of quinolinic acid lesions of the striatum

TSPO 18 kDa (PBR) Targeted Photosensitizers for Cancer Imaging (PET) and PDT

Synthesis of [123I]iodine labelled imidazo[1,2-b] pyridazines as potential probes for the study of peripheral benzodiazepine receptors using SPECT

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Synaptic localization of GABA_A receptor subunits in the substantia nigra of the rat: effects of quinolinic acid lesions of the striatum

Synaptic localization of GABA_A receptor subunits in the substantia nigra of the rat: effects of quinolinic acid lesions of the striatum

Synthesis of [¹²³I]iodine labelled imidazo[1,2-b] pyridazines as potential probes for the study of peripheral benzodiazepine receptors using SPECT