title: Pharmaceutical development of novel lactate-based 6-fluoro-l-DOPA formulations.
abstract: 6-[18F]fluoro-l-dihydroxyphenylalanine (18F-DOPA) is a diagnostic positron emission tomography (PET) agent, which has been used for decades in imaging the loss of dopaminergic neurons in Parkinson's disease, and more recently to detect, stage and restage neuroendocrine tumors (NETs) and to search for recurrence of viable glioma tissue. The commercially available18F-DOPA PET radiopharmaceutical for diagnostic use in European Union countries, is formulated in an aqueous solution of acetic acid (1.05mg/mL) and has the disadvantages that, immediately before injection, the pH must be adjusted to 4.0-5.0 by the addition of a sterile solution of sodium bicarbonate (84mg/mL) causing a light and transient burning sensation at the injection site. To overcome these drawbacks, preformulation studies were accomplished to confirm that F-DOPA degradation was affected by pH. Hence, two formulations of F-DOPA, namely ND1 and ND2, were prepared maintaining the pH=5.0 using 1mM l-(+)-lactate buffer, excluding oxygen, and incorporating in the formula the chelating agent Na2EDTA (1mM). F-DOPA oxygen exposure, the presence of free metal cations in formulation and high pH values seem to promote F-DOPA degradation. The resulting formulations proved to guarantee the chemical stability of F-DOPA in solution at pH5.0, value also compatible with the direct infusion. In vitro cell viability tests on mouse skeletal muscle fibers, renal tsa201 and neuronal SH-SY5Y cell lines, and in vivo studies in rats reported elsewhere, showed cell tolerability to the new F-DOPA formulations providing the basis for their further in vivo evaluation.
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy. Electronic address: nunzio.denora@uniba.it.
authors.forename: Nunzio
authors.initials: N
authors.lastname: Denora
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Lopedota
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Modesto
authors.initials: M
authors.lastname: de Candia
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Saverio
authors.initials: S
authors.lastname: Cellamare
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Degennaro
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Renzo
authors.initials: R
authors.lastname: Luisi
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Mele
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Tricarico
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Cutrignelli
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Valentino
authors.initials: V
authors.lastname: Laquintana
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Cosimo D
authors.initials: CD
authors.lastname: Altomare
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Franco
authors.affiliation: Itel Telecomunicazioni srl - Radiopharmaceutical Business Unit, Via Antonio Labriola lotto 39 z.i., 70037 Ruvo di Puglia (BA), Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Dimiccoli
authors.affiliation: Itel Telecomunicazioni srl - Radiopharmaceutical Business Unit, Via Antonio Labriola lotto 39 z.i., 70037 Ruvo di Puglia (BA), Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Tolomeo
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, 70125 Bari, Italy. Electronic address: antonio.scilimati@uniba.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Scilimati
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004295:Dihydroxyphenylalanine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000737:chemistry*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000737:chemistry; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000008:administration & dosage* / Q000737:chemistry*; D051381:Rats
chemical_list: D019275:Radiopharmaceuticals; C043437:fluorodopa F 18; D019344:Lactic Acid; D004295:Dihydroxyphenylalanine; D010100:Oxygen
keywords: 6-Fluoro-l-dopa (F-DOPA); F-DOPA stability; Formulation; In vitro and in vivo studies; Positron emission tomography (PET); l-(+)-lactic acid; pH-rate profile