Synthesis of 11C-labelled benzamide compounds as potential tracers for poly(ADP-ribose) synthetase

doi:10.1016/0969-8043(94)90251-8

Applied Radiation and Isotopes

Volume 45, Issue 6, June 1994, Pages 707-714

https://doi.org/10.1016/0969-8043(94)90251-8 Get rights and content

Abstract

Poly (ADP-ribose) synthetase catalyses the synthesis of poly (ADP-ribose) from NAD⁺, thereby releasing the DNA from histones to a transcriptionally and reparationally active form. In order to investigate if in vivo and in vitro studies of this enzyme are feasible to perform with PET, the poly (ADP-ribose) synthetase inhibitors benzamide, 3-aminobenzamide, 3-methoxybenzamide and nicotinamide were labelled with carbon-11 in the amide group. Starting with the corresponding aromatic halides and hydrogen [¹¹C]cyanide, the substituted [¹¹C]benzonitriles were prepared using a palladium promoted reaction. Conversion of the nitriles to [carboxy-¹¹C]amides was achieved by reaction with sodium percarbonate. A one-pot procedure for the synthesis of the ¹¹C-labelled aromatic amides was developed. The total synthesis time including reversed-phase HPLC purification was 25–35 min. Decay-corrected radiochemical yield was 45–70% and the radiochemical purity < 99%. The specific radioactivity was in the order of 2–3 Ci · μmol⁻¹.

Initial distribution and kinetic studies were performed in monkey using the tracer substance injected as a rapid bolus. These studies demonstrated that the blood-clearance was fast for [carboxy-¹¹C]nicotinamide but considerably slower for 3-amino[carboxy-¹¹C]benzamide and 3-methoxy[carboxy-¹¹C]benzamide. The brain uptake was low for all substances except 3-methoxy[carboxy-¹¹C]benzamide which initially had a high brain uptake, followed by a rapid wash out. The ¹¹C-labelled nicotinamide demonstrated a rapid fixation with high uptake values in the liver, kidney and lymph nodes.

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Radiolabeling with [11C]HCN for Positron emission tomography
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Citation Excerpt :
This method allows the authors to synthesize the three targeted compounds in useful yields of 45–66% decay-corrected yield in 25–35 min [116]. Benzamide (213), methoxybenzamide (214), aminobenzamide (215), and nicotinamide (216) are known to be potent inhibitors of poly (ADPribose) synthetase (Fig. 32), a common target for anticancer drugs and could be used to evaluate the amount DNA damage that occurs during treatments with radiotherapy or chemotherapy [116]. Compounds 214, 215, and 216 were studied in vivo in a rhesus monkey model.
Hydrogen cyanide (HCN) is a versatile synthon for generating carbon‑carbon and carbon-heteroatom bonds. Unlike other one-carbon synthons (i.e., CO, CO₂), HCN can function as a nucleophile (as in potassium cyanide, KCN) and an electrophile (as in cyanogen bromide, (CN)Br). The incorporation of the CN motif into organic molecules generates nitriles, hydantoins and (thio)cyanates, which can be converted to carboxylic acids, aldehydes, amides and amines. Such versatile chemistry is particularly attractive in PET radiochemistry where diverse bioactive small molecules incorporating carbon-11 in different positions need to be produced. The first examples of making [¹¹C]HCN for radiolabeling date back to the 1960s. During the ensuing decades, [¹¹C]cyanide labeling was popular for producing biologically important molecules including ¹¹C-labeled α-amino acids, sugars and neurotransmitters. [¹¹C]cyanation is now reemerging in many PET centers due to its versatility for making novel tracers. Here, we summarize the chemistry of [¹¹C]HCN, review the methods to make [¹¹C]HCN past and present, describe methods for labeling different types of molecules with [¹¹C]HCN, and provide an overview of the reactions available to convert nitriles into other functional groups. Finally, we discuss some of the challenges and opportunities in [¹¹C]HCN labeling such as developing more robust methods to produce [¹¹C]HCN and developing rapid and selective methods to convert nitriles into other functional groups in complex molecules.
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For example, starting from 11COCl2, the synthesis of [11C]carbamoyl chlorides has been achieved [64], which could then be transformed into 11C-labeled urea, carbamate, or amide derivatives [71]. [ 11C]HCN is the starting material for 11C-cyanation reactions and can be used directly to introduce 11CN group to the desired molecule, which could then be converted into a wide range of other functional groups, such as carboxylic acids, amides, tetrazoles, and amidines [72–77]. For example, it is well established that [11C]amino acids could be obtained using the Bucherer-Strecker synthesis starting from 11CN− [78–83].
Molecular imaging is an emerging technology that allows the visualization of interactions between molecular probes and biological targets. Molecules that either direct or are subject to homeostatic controls in biological systems could be labeled with the appropriate radioisotopes for the quantitative measurement of selected molecular interactions during normal tissue homeostasis and again after perturbations of the normal state. In particular, positron emission tomography (PET) offers picomolar sensitivity and is a fully translational technique that requires specific probes radiolabeled with a usually short-lived positron-emitting radionuclide. PET has provided the capability of measuring biological processes at the molecular and metabolic levels in vivo by the detection of the gamma rays formed as a result of the annihilation of the positrons emitted. Despite the great wealth of information that such probes can provide, the potential of PET strongly depends on the availability of suitable PET radiotracers. However, the development of new imaging probes for PET is far from trivial and radiochemistry is a major limiting factor for the field of PET. In this review, we provided an overview of the most common chemical approaches for the synthesis of PET-labeled molecules and highlighted the most recent developments and trends. The discussed PET radionuclides include ¹¹C (t_1/2 = 20.4 min), ¹³N (t_1/2 = 9.9 min), ¹⁵O (t_1/2 = 2 min), ⁶⁸Ga (t_1/2 = 68 min), ¹⁸F (t_1/2 = 109.8 min), ⁶⁴Cu (t_1/2 = 12.7 h), and ¹²⁴I (t_1/2 = 4.12 d).
PISA, A novel pharmacodynamic assay for assessing poly(ADP-ribose) polymerase (PARP) activity in situ
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Poly ADP-ribose polymerase (PARP) maintains genomic integrity by repairing DNA strand breaks, however over-activation of PARP following neural tissue injury is hypothesized to cause neuronal death. Therefore, PARP inhibitors have potential for limiting neural injury under certain conditions. A reliable method for assessing PARP activity in brain is critical for development of novel inhibitors with CNS activity. We developed the PARP In Situ Activity (PISA) assay to provide a direct, quantitative assessment of CNS PARP activity in vitro or in vivo.
The assay utilized brain sections from rats with striatal kainic acid (KA) lesions and ³H- or biotinylated NAD⁺ as the substrate to assess PARP activity. Following optimization of the assay, it was used to assess in vitro and in vivo efficacy of known and novel PARP inhibitors. The assay also was used to assess PARP activity in male and female gonad-intact and ovariectomized rats.
Using ³H-NAD⁺ as the substrate, PARP activity was greater (p < 0.01) in tissue from KA-lesioned vs. non-lesioned rats. Using biotinylated NAD⁺ it was revealed that PARP activity was present ipsilateral to the KA injection site, and labeling was blocked by incubation with excess unlabeled NAD⁺ or PARP inhibitors. The PARP inhibitor, 3-aminobenzamide and several novel inhibitors reduced (p < 0.01) polymerase activity in vitro. Furthermore, the inhibitor MRLSD303 reduced (p < 0.001) PARP activity in vivo in both male and female rats. Finally, administration of the novel PARP inhibitor MRLIT115 dose-dependently reduced (p < 0.001) polymerase activity in vivo.
The PISA assay provides a direct, quantitative method for assessing PARP activity in vitro and provides critical information on factors underlying in vivo efficacy of chemical inhibitors including brain penetration and target engagement. These findings support use of the PISA assay as a screening tool for testing efficacy of PARP inhibitors in brain.
Biodistribution and pharmacokinetics of the 19F-labeled radiosensitizer 3-aminobenzamide: Assessment by 19F MR imaging
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3-Aminobenzamide (3-ABA) is a potent radiosensitizer that inhibits the repair of DNA strand breaks. The aim of this study was to monitor the biodistribution and pharmacokinetics of a fluorinated 3-ABA derivative in tumor-bearing rats by magnetic resonance imaging (MRI). To this end, 3-ABA was labeled with fluorine-19 by trifluoroethylation [3-amino-N-2,2,2-trifluoroethylbenzamide (3-ABA-TFE)], which only slightly increased the cytotoxicity of the compound as demonstrated by colony-forming assays. After intraperitoneal injection of 400 mg/kg BW 3-ABA-TFE to nine Copenhagen rats with Dunning prostate adenocarcinoma, ¹⁹F MR images were acquired at a whole-body MR system with a spatial sampling of 10×10×15 mm³. While 3-ABA-TFE was observed in all major organs and the muscular system, only a small and heterogeneous signal could be detected in the adenocarcinoma. Serial MR measurements yielded maximum tissue signals about 2 days after 3-ABA-TFE administration. At this time point, the mean muscle-to-liver and tumor-to-liver signal ratio was 0.31±0.07 and 0.11±0.04, respectively. Application of the ¹⁹F MRI strategy makes it possible to measure the biodistribution and pharmacokinetics of 3-ABA-TFE in individual animals in a longitudinal manner. The results obtained for the prostate adenocarcinoma indicate that delivery of 3-ABA-TFE to solid tumors may be seriously hampered by tumor-specific factors and that the intratumoral uptake of the substance may be lower than in normal tissues. Therefore, the development of effective carrier systems is mandatory to improve tumor-selective delivery.
Neuroprotective effects of KCL-440, a new poly(ADP-ribose) polymerase inhibitor, in the rat middle cerebral artery occlusion model
2005, Brain Research
Citation Excerpt :
The IC50 value of KCL-440 was 68 nM, which was 4 and 1000 times more potent than that of PJ-34 and 3-AB, respectively; further, using 50 μM of Km for NAD, the calculated value of Ki was found to be 9.8 nM [10]. In addition, 3-AB does not pass the blood–brain barrier after peripheral administration [3,24], whereas a beneficial brain:serum concentration ratio of KCL-440 was observed after its continuous infusion of KCL-440. This pharmacokinetic property of KCL-440 makes it favorable for the purpose of intravenous administration.
It is reported that ischemic brain injury is mediated by the activation of poly(ADP-ribose) polymerase (PARP). In this study, we examined the pharmacological profile of KCL-440, a new PARP inhibitor, and its neuroprotective effects in the rat acute cerebral infarction model induced by photothrombotic middle cerebral artery (MCA) occlusion. In an in vitro study, KCL-440 exhibited potency with regard to inhibition of PARP activity, with an IC₅₀ value of 68 nM. An in vivo pharmacokinetic study showed that the brain concentration of KCL-440 was sufficient to inhibit PARP activity during the intravenous infusion of KCL-440 at the rate of 1 mg/kg/h. KCL-440 at various doses or saline was administered for 24 h immediately after the MCA occlusion. Administration of KCL-440 led to a dose-dependent reduction in the infarct size at 24 h after MCA occlusion. Infarct sizes were 44.8% ± 3.0% (n = 8), 40.5% ± 1.1% (n = 8), 38.2% ± 1.4% (n = 8), 35.1% ± 2.1% (n = 8), 34.2% ± 2.3% (n = 7), 32.6% ± 1.9% (n = 8), and 31.0% ± 2.1% (n = 5) at doses of 0, 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg/h. When compared to the control group, a statistically significant difference was observed in the doses that were higher than 0.03 mg/kg/h. When the infusion of KCL-440 (1 mg/kg/h, n = 8) was started at 1 h after the MCA occlusion, a significant reduction in infarct size was observed; this was not observed when KCL-440 infusion was started 2 or 3 h after the MCA occlusion. Furthermore, increased poly(ADP-ribose) immunostaining was confirmed at the ischemic border zone 2 h after the MCA occlusion, and it was reduced by KCL-440 treatment. These results suggest that KCL-440 is a possible neuroprotective agent with high blood–brain barrier permeability and high PARP inhibitory activity.
Biodistribution of 3,4-dihydro-5-[11C]methoxy-1(2H)-isoquinolinone, a potential PET tracer for poly(ADP-ribose) synthetase
2000, Nuclear Medicine and Biology
Poly(adenosine diphosphate-ribose) synthetase (PARS) is a nuclear enzyme that is activated by deoxyribonucleic acid (DNA) strand breaks and participates in DNA repair. Excessive PARS activation, however, leads to cell death due to depletion of adenosine triphosphate (ATP). To evaluate whether it is possible to detect excessive activation of PARS with positron emission tomography (PET), we examined the pharmacokinetics of 3,4-dihydro-5-[¹¹C]methoxy-1(2H)-isoquinolinone ([¹¹C]MIQO), a potent poly(ADP-ribose) synthetase inhibitor, in the brain of rats and monkeys. Although the uptake of [¹¹C]MIQO in the brain of normal rats was low, [¹¹C]MIQO was rapidly incorporated into and then quickly washed out from the brain. The uptake of the radiotracer in the brain of normal monkeys was also low; however, [¹¹C]MIQO gave a distribution image that differed from that of cerebral blood flow obtained by [¹⁵O]water-PET. No localization of [¹¹C]MIQO in the brain of normal monkeys was observed. Low accumulation of some radioactivity was also observed in muscles surrounding the brain of monkeys, but did not seem to interfere with measurement of [¹¹C]MIQO uptake in the brain with PET. Thus, detection of [¹¹C]MIQO uptake with PET may be useful for detecting PARS activity in ischemic injury.

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Applied Radiation and Isotopes

Abstract

References (13)

Specific inhibitors of poly-(ADP-ribose) synthetase and mono (ADP-ribose) transferase

J. Biol. Chem.

Scandium, chromium (VI), gallium, yttrium, rhodium, palladium, indium in mice: effects on growth and life span

J. Nutr.

The use of organometallic compounds in synthesis of ¹¹C-labelled aromatics

J. Label. Compds Radio-pharmac.

Relation between carcinogenesis, chromatin structure and poly (ADP-ribosylation)

Anticancer Res.

Palladium-catalyzed cyanation of aryl halides by trimethylsilyl chanide

J. Org. Chem.

Cyanation of aromatic halides

Chem. Rev.

Cited by (29)

Radiolabeling with [<sup>11</sup>C]HCN for Positron emission tomography

Radiopharmaceutical chemistry for positron emission tomography

PISA, A novel pharmacodynamic assay for assessing poly(ADP-ribose) polymerase (PARP) activity in situ

Biodistribution and pharmacokinetics of the <sup>19</sup>F-labeled radiosensitizer 3-aminobenzamide: Assessment by <sup>19</sup>F MR imaging

Neuroprotective effects of KCL-440, a new poly(ADP-ribose) polymerase inhibitor, in the rat middle cerebral artery occlusion model

Biodistribution of 3,4-dihydro-5-[<sup>11</sup>C]methoxy-1(2H)-isoquinolinone, a potential PET tracer for poly(ADP-ribose) synthetase

Synthesis of 11C-labelled benzamide compounds as potential tracers for poly(ADP-ribose) synthetase

Abstract

J. Biol. Chem.

J. Nutr.

The use of organometallic compounds in synthesis of 11C-labelled aromatics

J. Label. Compds Radio-pharmac.

Relation between carcinogenesis, chromatin structure and poly (ADP-ribosylation)

Anticancer Res.

Palladium-catalyzed cyanation of aryl halides by trimethylsilyl chanide

J. Org. Chem.

Cyanation of aromatic halides

Chem. Rev.

Synthesis of ¹¹C-labelled benzamide compounds as potential tracers for poly(ADP-ribose) synthetase

The use of organometallic compounds in synthesis of ¹¹C-labelled aromatics