Synthesis and evaluation in rats of homologous series of [18F]-labeled dopamine D2/3 receptor agonists based on the 2-aminomethylchroman scaffold as potential PET tracers

Shalgunov, Vladimir; Wieringen, Jan-Peter van; Janssen, Henk M.; Fransen, Peter; Dierckx, Rudi; Michel, Martin C.; Booij, Jan; Elsinga, Philip H.

doi:10.1186/s13550-015-0119-x

Cited by 6 publications

(8 citation statements)

References 33 publications

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“…Many cellular genetic and epigenetic factors affect the sensitivity of each tumor to radiotherapy approaches. Recently, the tumor stroma component has been found to play a key role in the outcome of irradiated tumors (1). When radiotherapy is prescribed to a patient, it is assumed that the normal nonmalignant tissue will also be irradiated giving rise to multifarious biological effects including inflammation and scarring (1).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, the tumor stroma component has been found to play a key role in the outcome of irradiated tumors (1). When radiotherapy is prescribed to a patient, it is assumed that the normal nonmalignant tissue will also be irradiated giving rise to multifarious biological effects including inflammation and scarring (1). Radiotherapy can be performed by applying an external beam of irradiation or by the temporal surgical insertion of radiation sources guided by catheters into the cancer tissue using techniques collectively known as brachytherapy.…”

Section: Introductionmentioning

confidence: 99%

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Abscopal Effects of Radiotherapy Are Enhanced by Combined Immunostimulatory mAbs and Are Dependent on CD8 T Cells and Crosspriming

et al. 2016

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Preclinical and clinical evidence indicate that the proimmune effects of radiotherapy can be synergistically augmented with immunostimulatory mAbs to act both on irradiated tumor lesions and on distant, nonirradiated tumor sites. The combination of radiotherapy with immunostimulatory anti-PD1 and anti-CD137 mAbs was conducive to favorable effects on distant nonirradiated tumor lesions as observed in transplanted MC38 (colorectal cancer), B16OVA (melanoma), and 4T1 (breast cancer) models. The therapeutic activity was crucially performed by CD8 T cells, as found in selective depletion experiments. Moreover, the integrities of BATF-3-dependent dendritic cells specialized in crosspresentation/crosspriming of antigens to CD8þ T cells and of the type I IFN system were absolute requirements for the antitumor effects to occur. The irradiation regimen induced immune infiltrate changes in the irradiated and nonirradiated lesions featured by reductions in the total content of effector T cells, Tregs, and myeloid-derived suppressor cells, while effector T cells expressed more intracellular IFNg in both the irradiated and contralateral tumors. Importantly, 48 hours after irradiation, CD8 þ TILs showed brighter expression of CD137 and PD1, thereby displaying more target molecules for the corresponding mAbs. Likewise, PD1 and CD137 were induced on tumor-infiltrating lymphocytes from surgically excised human carcinomas that were irradiated ex vivo. These mechanisms involving crosspriming and CD8 T cells advocate clinical development of immunotherapy combinations with anti-PD1 plus anti-CD137 mAbs that can be synergistically accompanied by radiotherapy strategies, even if the disease is left outside the field of irradiation.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Abscopal Effects of Radiotherapy Are Enhanced by Combined Immunostimulatory mAbs and Are Dependent on CD8 T Cells and Crosspriming

et al. 2016

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“…Apomorphine analogs, 11 C-NPA in PET studies of nonhuman primates clearly showed binding to the caudate-putamen, similar to that found for 11 C-raclopride (Finnema et al, 2009; Hwang et al, 2005). More recently, agonists 18 F-MCL-524, apomorphine analogs (Finnema et al, 2014; Sromek et al, 2014) and 18 F-aminomethylchroman analogs (Shalgunov et al, 2015a,b) have been reported for imaging dopamine D2 and D3 receptors. 11 C-PHNO is a modified aminotetralin derivative and has high-affinity for D2 and D3 receptor subtypes thus suggesting that PHNO binds to D2-high affinity state (HA) and D3 receptors.…”

Section: | Introductionmentioning

confidence: 99%

PET radiotracer development for imaging high‐affinity state of dopamine D2 and D3 receptors: Binding studies of fluorine‐18 labeled aminotetralins in rodents

Majji

Kaur

Constantinescu

et al. 2016

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Imaging the high-affinity, functional state (HA) of dopamine D2 and D3 receptors has been pursued in PET imaging studies of various brain functions. We report further evaluation of 18F-5-OH-FPPAT, and the newer 18F-5-OH-FHXPAT and 18F-7-OH-FHXPAT. Syntheses of 18F-5-OH-FHXPAT and 18F-7-OH-FHXPAT were improved by modifications of our previously reported procedures. Brain slices and brain homogenates from male Sprague-Dawley rats were used with the 3 radiotracers (74–111 kBq/cc). Competition with dopamine (1–100 nM) and Gpp(NH)p (10–50 μM) were carried out to demonstrate binding to dopamine D2 and D3 HA-states and binding kinetics of 18F-5-OH-FPPAT measured. Ex vivo brain slice autoradiography was carried out on rats administered with 18F-5-OH-FHXPAT to ascertain HA-state binding. PET/CT imaging in rats and wild type (WT) and D2 knock-out mice were carried out using 18F-7-OH-FHXPAT (2–37 MBq). Striatum was clearly visualized by the three radiotracers in brain slices and dopamine displaced more than 80% of binding, with dissociation rate in homogenates of 2.2 × 10−2 min−1 for 18F-5-OH-FPPAT. Treatment with Gpp(NH)p significantly reduced 50–80% striatal binding with faster dissociation rates (5.0 × 10−2 min−1), suggesting HA-state binding of 18F-5-OH-FPPAT and 18F-5-OH-FHXPAT. Striatal binding of 18F-5-OH-FHXPAT in ex vivo brain slices were sensitive to Gpp(NH)p, suggesting HA-state binding in vivo. PET binding ratios of 18F-7-OH-FHXPAT in rat brain were ventral striatum/cerebellum=2.09 and dorsal striatum/cerebellum=1.65; similar binding ratios were found in the D2 WT mice. These results suggest that in vivo PET measures of agonists in the brain at least in part reflect binding to the membrane-bound HA-state of the dopamine receptor.

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“…3 were synthesised by O-alkylation of the phenolic precursor with 150. 49,68,80,89,99,100,[137][138][139][140] The alkylation reactions were performed in DMSO, DMF or MeCN at around 100 1C and different bases were employed (NaH, NaOH, K 2 CO 3 or TBAOH). The precursor of the serotonin transporter ligand 167 was pre-incubated with the base prior to [ 18 F]fluoropropylation to form the phenolate, thereby facilitating nucleophilic substitution.…”

Section: [ 18 F]fluoroformmentioning

confidence: 99%

“…Using building block 151, resulted in increased lipophilicity of the tracer and thereby enhanced ability to penetrate the blood brain barrier. 100,113 Also, four tropane derivatives, 171a-c and 172, were developed for imaging the dopamine transporter. The fluoroalkylation reactions could be carried out without base catalysis.…”

Section: [ 18 F]fluoroformmentioning

confidence: 99%

Fluorine-18 labelled building blocks for PET tracer synthesis

et al. 2017

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Positron emission tomography (PET) is an important driver for present day healthcare. Fluorine-18 is the most widely used radioisotope for PET imaging and a thorough overview of the available radiochemistry methodology is a prerequisite for selection of a synthetic approach for new fluorine-18 labelled PET tracers. These PET tracers can be synthesised either by late-stage radiofluorination, introducing fluorine-18 in the last step of the synthesis, or by a building block approach (also called modular build-up approach), introducing fluorine-18 in a fast and efficient manner in a building block, which is reacted further in one or multiple reaction steps to form the PET tracer. This review presents a comprehensive overview of the synthesis and application of fluorine-18 labelled building blocks since 2010.

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Synthesis and evaluation in rats of homologous series of [18F]-labeled dopamine D2/3 receptor agonists based on the 2-aminomethylchroman scaffold as potential PET tracers

Cited by 6 publications

References 33 publications

Abscopal Effects of Radiotherapy Are Enhanced by Combined Immunostimulatory mAbs and Are Dependent on CD8 T Cells and Crosspriming

Abscopal Effects of Radiotherapy Are Enhanced by Combined Immunostimulatory mAbs and Are Dependent on CD8 T Cells and Crosspriming

PET radiotracer development for imaging high‐affinity state of dopamine D2 and D3 receptors: Binding studies of fluorine‐18 labeled aminotetralins in rodents

Fluorine-18 labelled building blocks for PET tracer synthesis

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