Ascending single-dose study of the safety, pharmacokinetics, and pharmacodynamics of CSTI-500, a novel monoamine triple reuptake inhibitor, first-in-human.
Rationale: Monoamine triple reuptake inhibitors (TRIs) inhibit central dopamine, norepinephrine, and serotonin transporters, restoring functional monoamine neurotransmission. Objectives: This clinical trial evaluated the safety, tolerability, and pharmacokinetics in healthy volunteers after single-a...
| Publicado en: | Psychopharmacology Vol. 243; no. 3; pp. 565 - 581 |
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| Autores principales: | , , , , , , |
| Formato: | Journal Article |
| Publicado: |
Springer Nature
Mar2026
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=192231477&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 192231477 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00333158 EJD jtl: Psychopharmacology issn: 00333158 maglogo: N pubinfo: dt: Mar2026 vid: 243 iid: 3 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 192231477 187227343 10.1007/s00213-025-06861-4 192231477 ppf: 565 ppct: 16 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Ascending single-dose study of the safety, pharmacokinetics, and pharmacodynamics of CSTI-500, a novel monoamine triple reuptake inhibitor, first-in-human. aug: au: Appel, Lieuwe Risinger, Robert Wall, Anders Murck, Harald Liu, Shuang Antoni, Gunnar Lane, Roger affil: https://ror.org/048a87296 Molecular Imaging and Medical Physics, Department of Surgical Sciences, Uppsala University, Uppsala, Sweden sug: ab: Rationale: Monoamine triple reuptake inhibitors (TRIs) inhibit central dopamine, norepinephrine, and serotonin transporters, restoring functional monoamine neurotransmission. Objectives: This clinical trial evaluated the safety, tolerability, and pharmacokinetics in healthy volunteers after single-ascending-doses (SAD) of the novel monoamine TRI CSTI-500. In addition, we estimated the peak and duration of striatal serotonin transporter (SERT) and dopamine transporter (DAT) occupancies, by using positron emission tomography (PET). Methods: Part A was a double-blinded, randomized, placebo-controlled, sequential SAD study with seven sequential dose panels (0.5-150 mg) where subjects in each panel received either a single oral dose of CSTI-500 (n=6) or placebo (n=2). Part B was an open-label, single-dose PET study to assess the peak and duration of SERT (n=4) and DAT (n=5) striatal occupancies, using the radioligands [11C]MADAM and [11C]PE2I, respectively. Results: The maximum tolerable acute single-dose of CSTI-500 was determined as 100 mg. No serious adverse events occurred. The median maximum CSTI-500 concentrations were attained at 1-2 hours post-dose (h pd); the estimated plasma elimination half-life was 44-50 h pd. Subsequent to a single-dose of 100 mg CSTI-500, mean striatal SERT occupancy was 72% and 62% at 4-6 and 24 h pd, respectively. Mean striatal DAT occupancy was 36% and 31% at 4-9 and 24 h pd, respectively. Conclusions: CSTI-500 is a potent monoamine TRI with substantial striatal SERT and moderate DAT occupancies in healthy subjects. Together with promising safety-tolerability and pharmacokinetics profiles, the continued clinical development of CSTI-500 is strongly supported. pubtype: Academic Journal doctype: Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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