Tissue Distribution Studies of [18f]haloperidol, [18f]-β-(4-fluorobenzoyl)propionic acid, and [82br]bromperidol by External Scintigraphy

Digenis, George A.; Vincent, Styliani H.; Kook, C; Reiman, Robert E.; Russ, Gerald A.; Tilbury, R.S.

doi:10.1002/jps.2600700904

Cited by 23 publications

(5 citation statements)

References 15 publications

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“…55, 2011 SYNERGISTIC DRUG COMBINATIONS FOR TUBERCULOSIS THERAPY 3867 been successfully used to cure XDR-TB patients within a therapeutic drug regimen (1,4,40). Similarly, butyrophenones (including bromperidol) accumulate largely in the lung tissues of animal models (16). Furthermore, lower dosages over longer periods may allow additional accumulation in lung macrophages, as suggested by our ex vivo experiments.…”

Section: Discussionmentioning

confidence: 74%

Synergistic Drug Combinations for Tuberculosis Therapy Identified by a Novel High-Throughput Screen

Ramón-García

Anderson

et al. 2011

Antimicrob Agents Chemother

155

129

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Therapeutic options for tuberculosis (TB) are limited and notoriously ineffective despite the wide variety of potent antibiotics available for treating other bacterial infections. We investigated an approach that enables an expansion of TB therapeutic strategies by using synergistic combinations of drugs. To achieve this, we devised a high-throughput synergy screen (HTSS) of chemical libraries having known pharmaceutical properties, including thousands that are clinically approved. Spectinomycin was used to test the concept that clinically available antibiotics with limited efficacy against Mycobacterium tuberculosis might be used for TB treatment when coadministered with a synergistic partner compound used as a sensitizer. Screens using Mycobacterium smegmatis revealed many compounds in our libraries that acted synergistically with spectinomycin. Among them, several families of antimicrobial compounds, including macrolides and azoles, were also synergistic against M. tuberculosis in vitro and in a macrophage model of M. tuberculosis infection. Strikingly, each sensitizer identified for synergy with spectinomycin uniquely enhanced the activities of other clinically used antibiotics, revealing a remarkable number of unexplored synergistic drug combinations. HTSS also revealed a novel activity for bromperidol, a butyrophenone used as an antipsychotic drug, which was discovered to be bactericidal and greatly enhanced the activities of several antibiotics and drug combinations against M. tuberculosis. Our results suggest that many compounds in the currently available pharmacopoeia could be readily mobilized for TB treatment, including disease caused by multi- and extensively drug-resistant strains for which there are no effective therapies.

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Section: Discussionmentioning

confidence: 74%

Synergistic Drug Combinations for Tuberculosis Therapy Identified by a Novel High-Throughput Screen

Ramón-García

Anderson

et al. 2011

Antimicrob Agents Chemother

155

129

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“…This compound produced no neuroleptic effects in dogs or rats at doses up to 40 mg/kg. Digenis et al (1981) have synthesized P-(4-['8F]fluorobenzoyl)propionic acid, the first metabolite in the above proposed scheme for these IsFlabeled neuroleptics, and reported negligible brain uptake of radioactivity following peripheral injection of this compound into rats. These results indicate that radioactive metabolic products of these butyrophenone neuroleptics, once formed in the periphery, will not enter the brain to complicate the analyses of radioactivity distribution in the CNS.…”

Section: D Arnett Et a Lmentioning

confidence: 99%

Comparison of Three ¹⁸F‐Labeled Butyrophenone Neuroleptic Drugs in the Baboon Using Positron Emission Tomography

Arnett

Shiue

Wolf

et al. 1985

Journal of Neurochemistry

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The butyrophenone neuroleptics spiroperidol, benperidol, and haloperidol were radiolabeled with fluorine-18 and studied in baboon brain using positron emission transaxial tomography (PETT). Pretreatment of the baboon with a high pharmacological dose of (+)-butaclamol reduced the specifically bound component of radioactivity distribution in the striatum to approximately the radioactivity distribution found in the cerebellum. Comparative studies of brain distribution kinetics over a 4-h period indicated that either [18F]spiroperidol or [18F]benperidol may be suitable for specific labeling of neuroleptic receptors. In an 8-h study with [18F]spiroperidol, striatal radioactivity did not decline, suggesting that spiroperidol either has a very slow dissociation rate or that it binds irreversibly to these receptors in vivo. [18F]Haloperidol may not be suitable for in vivo PETT studies, because of a relatively high component of nonspecific distribution and a faster dissociation from the receptor. Analysis of 18F in plasma after injection of [18F]spiroperidol indicated rapid metabolism to polar and acidic metabolites, with only 40% of the total radioactivity being present as unchanged drug after 30 min. Analysis of the metabolic stability of the radioactively labeled compound in rat striatum indicated that greater than 95% of [18F]spiroperidol remains unchanged after 4 h.

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“…'*Br-Bromperidol (16)(17), "Br-bromspiroperidol (18)(19), "F-Haloperidol (17,20,21), "C- Spiroperidol (21), 75/77Br-Benperidol (22) and "C-MPTP (23). 3-N-["C]-methylspiperone, a ligand with high affinity for dopamine receptors, labeled with the positron-emitting radionuclide "C, has been used in imaging the receptors by positron emission tomography scanning in baboons and in humans (24,25).…”

Section: Introductionmentioning

confidence: 99%

“…The extract was filtered, and the solvent evaporated in vacuo. The product was recrystallized from benzene to yield 20 mg (18%) of 2a; mp 320-325 OC dec; NMR (CDCI,) S 2.55-2.63 (3H,s), 4.98-5 17. (2H,d), 7.20-7.42 (3H,m); M.S.…”

mentioning

confidence: 99%

Structure biodistribution relationship of radiolabeled ergolines: Search for brain imaging radiopharmaceuticals

Basmadjian

Sadek

Mikhail

et al. 1989

Labelled Comp Radiopharmac

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A series of ergoline derivatives, analogues of Pergolide 1 and Lysergol 6, were synthesized, radiolabeled with '=I or 75Se, and evaluated for their ability to cross the Blood Brain Barrier of rats, for potential use as radiopharmaceuticals for imaging the brain. Introduction of the radiolabel was either at the 17-position (attached to the SB-methylene) or at the 2-position of the indole portion of the ergoline moie Of the 8 radiolabeled compounds tested, two pergolide analogues, SB-(methyl%eseleno)-methyl-6-propyl ergoline 5 and 8B-['~I]-iodomethyl-6-propyl ergoline 2f showed the highest uptake in the brain, adrenal and heart with good organ to blood ratios. This work has shown that analogues of pergolide, a dopamine agonist, if labeled with '=I may yield a clinically useful brain imaging radiopharmaceutical. 1 2 5 , 9 J [O;I H,,, C H 2 7 6 S e [ 4cH2c 2 z. cn,i

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Tissue Distribution Studies of [18f]haloperidol, [18f]-β-(4-fluorobenzoyl)propionic acid, and [82br]bromperidol by External Scintigraphy

Cited by 23 publications

References 15 publications

Synergistic Drug Combinations for Tuberculosis Therapy Identified by a Novel High-Throughput Screen

Synergistic Drug Combinations for Tuberculosis Therapy Identified by a Novel High-Throughput Screen

Comparison of Three ¹⁸F‐Labeled Butyrophenone Neuroleptic Drugs in the Baboon Using Positron Emission Tomography

Structure biodistribution relationship of radiolabeled ergolines: Search for brain imaging radiopharmaceuticals

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Tissue Distribution Studies of [18f]haloperidol, [18f]-β-(4-fluorobenzoyl)propionic acid, and [82br]bromperidol by External Scintigraphy

Cited by 23 publications

References 15 publications

Synergistic Drug Combinations for Tuberculosis Therapy Identified by a Novel High-Throughput Screen

Synergistic Drug Combinations for Tuberculosis Therapy Identified by a Novel High-Throughput Screen

Comparison of Three 18F‐Labeled Butyrophenone Neuroleptic Drugs in the Baboon Using Positron Emission Tomography

Structure biodistribution relationship of radiolabeled ergolines: Search for brain imaging radiopharmaceuticals

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Comparison of Three ¹⁸F‐Labeled Butyrophenone Neuroleptic Drugs in the Baboon Using Positron Emission Tomography