High-yielding 18F radiosynthesis of a novel oxytocin receptor tracer, a probe for nose-to-brain oxytocin uptake in vivo

Rhiannon Beard, Nisha Singh, Christophe Grundschober, Antony D Gee, Edward W Tate, Rhiannon Beard, Nisha Singh, Christophe Grundschober, Antony D Gee, Edward W Tate

Abstract

A novel Al18F labelled peptide tracer for PET imaging of oxytocin receptor has been accessed through a high radiochemical yield approach. This tracer showed comparable affinity and higher selectivity and stability compared to oxytocin, and was used to demonstrate direct nose-to-brain uptake following intranasal administration, a common yet controversial delivery route for oxytocin-based therapeutics.

Figures

Fig. 1. Structure of OT (A), dLVT…
Fig. 1. Structure of OT (A), dLVT (B), OTR tracer precursor NODA-dLVT (C), and 18F radiolabelled tracer (D). Peptides contain a cyclic configuration due to the disulphide bond between positions 1 and 6. Key: dC = deaminated cysteine.
Fig. 2. Optimisation of 18 F radiolabelling…
Fig. 2. Optimisation of 18F radiolabelling of NODA-dLVT. (A) Elution profile of [18F]NaF with 0.9% (dashed) or 20% (solid) saline from anion exchange resin in 100 μL fractions, mean of 5 samples for each condition. Radiochemical conversion (RCC) for [18F]AlF labelling of NODA-dLVT (72 nmol) using 0.9% (B) or 20% (C) saline with different molar equivalents of aluminium chloride at 105 °C for 15 min. Values represent mean of 3 samples.
Fig. 3. Specific binding profile of […
Fig. 3. Specific binding profile of [18F]AlF-NODA-dLVT. Radiograms of total (top; 3 nM [18F]AlF-NODA-dLVT) and nonspecific binding (bottom; 3 nM [18F]AlF-NODA-dLVT and 10 μM OT) of [18F]AlF-NODA-dLVT to rat brain slices in the sagittal pane. Areas with high specific binding are indicated on the figure with arrow heads. Key: AO = anterior olfactory nucleus; CA1 = field CA1 of the hippocampus; Acb = accumbens nuclei; Tu = olfactory tubercle; VMH = ventromedial hypothalamic nuclei; MC = motor cortex; V1 = primary visual cortex; S = subiculum; ac = central amygdala nucleus; lo = lateral olfactory tract.
Fig. 4. Biodistribution of [ 18 F]AlF-NODA-dLVT…
Fig. 4. Biodistribution of [18F]AlF-NODA-dLVT in rat. (A) Shows biodistribution in major peripheral organs, while (B) shows uptake of [18F]AlF-NODA-dLVT in central nervous system regions. Both are shown relative to blood levels following either i.n. (30 min) or i.v. (10 min) administration. Each data point corresponds to mean ± SD, n = 3.

References

    1. Gimpl G., Fahrenholz F. Physiol. Rev. 2001;81:629–683.
    1. Pedersen C. A., Gibson C. M., Rau S. W., Salimi K., Smedley K. L., Casey R. L., Leserman J., Jarskog L. F., Penn D. L. Schizophr. Res. 2011;132:50–53.
    1. Penagarikano O., Lazaro M. T., Lu X. H., Gordon A., Dong H., Lam H. A., Peles E., Maidment N. T., Murphy N. P., Yang X. W., Golshani P., Geschwind D. H. Sci. Transl. Med. 2015;7:1–12.
    1. Hollander E., Novotny S., Hanratty M., Yaffe R., DeCaria C. M., Aronowitz B. R., Mosovich S. Neuropsychopharmacology. 2003;28:193–198.
    1. Quintana D. S., Guastella A. J., Westlye L. T., Andreassen O. A. Mol. Psychiatry. 2016;21:29–38.
    1. Andari E., Duhamel J. R., Zalla T., Herbrecht E., Leboyer M., Sirigu A. Proc. Natl. Acad. Sci. U. S. A. 2010;107:4389–4394.
    1. Watanabe T., Abe O., Kuwabara H., Yahata N., Takano Y., Iwashiro N., Natsubori T., Aoki Y., Takao H., Kawakubo Y., Kamio Y., Kato N., Miyashita Y., Kasai K., Yamasue H. JAMA Psychiatry. 2014;71:166–175.
    1. Guastella A. J., Gray K. M., Rinehart N. J., Alvares G. A., Tonge B. J., Hickie I. B., Keating C. M., Cacciotti-Saija C., Einfeld S. L. J. Child Psychol. Psychiatry. 2015;56:444–452.
    1. Dadds M. R., MacDonald E., Cauchi A., Williams K., Levy F., Brennan J. J. Autism Dev. Disord. 2014;44:521–531.
    1. Dufes C., Olivier J. C., Gaillard F., Gaillard A., Couet W., Muller J. M. Int. J. Pharm. 2003;255:87–97.
    1. Jacobson O., Kiesewetter D. O., Chen X. Bioconjugate Chem. 2015;26:1–18.
    1. McBride W. J., Sharkey R. M., Karacay H., D'Souza C. A., Rossi E. A., Laverman P., Chang C. H., Boerman O. C., Goldenberg D. M. J. Nucl. Med. 2009;50:991–998.
    1. McBride W. J., D’Souza C. A., Sharkey R. M., Karacay H., Rossi E. A., Chang C. H., Goldenberg D. M. Bioconjugate Chem. 2010;21:1331–1340.
    1. Terrillon S., Cheng L. L., Stoev S., Mouillac B., Barberis C., Manning M., Durroux T. J. Med. Chem. 2002;45:2579–2588.
    1. Chini B., Chinol M., Cassoni P., Papi S., Reversi A., Areces L., Marrocco T., Paganelli G., Manning M., Bussolati G. Br. J. Cancer. 2003;89:930–936.
    1. Gazis D. Proc. Soc. Exp. Biol. Med. 1978;158:663–665.
    1. Sharma K. S., Durand G., Giusti F., Olivier B., Fabiano A.-S., Bazzacco P., Dahmane T., Ebel C., Popot J.-L., Pucci B. Langmuir. 2008;24:13581–13590.
    1. Malik N., Zlatopolskiy B., Machulla H.-J., Reske S. N., Solbach C. J. Labelled Compd. Radiopharm. 2012;55:320–325.
    1. D’Souza C. A., McBride W. J., Sharkey R. M., Todaro L. J., Goldenberg D. M. Bioconjugate Chem. 2011;22:1793–1803.
    1. Heskamp S., Laverman P., Rosik D., Boschetti F., van der Graaf W. T., Oyen W. J., van Laarhoven H. W., Tolmachev V., Boerman O. C. J. Nucl. Med. 2012;53:146–153.
    1. Hausner S. H., Bauer N., Sutcliffe J. L. Nucl. Med. Biol. 2014;41:43–50.
    1. Liu S., Liu H., Jiang H., Xu Y., Zhang H., Cheng Z. Eur. J. Nucl. Med. Mol. Imaging. 2011;38:1732–1741.
    1. Freund-Mercier M. J., Stoeckel M. E., Palacios J. M., Pazos A., Reichhart J. M., Porte A., Richard P. Neuroscience. 1987;20:599–614.
    1. Tribollet E., Barberis C., Jard S., Dubois-Dauphin M., Dreifuss J. J. Brain Res. 1988;442:105–118.
    1. De Kloet E. R., Rotteveel F., Voorhuis T. A. M., Terlou M. Eur. J. Pharmacol. 1985;110:113–119.
    1. Tribollet E., Audigier S., Dubois-Dauphin M., Dreifuss J. J. Brain Res. 1990;511:129–140.
    1. Weisman O., Zagoory-Sharon O., Feldman R. Psychoneuroendocrinology. 2012;37:1582–1586.
    1. Neumann I. D., Maloumby R., Beiderbeck D. I., Lukas M., Landgraf R. Psychoneuroendocrinology. 2013;38:1985–1993.
    1. Sjöholm I., Rydén G. Acta Endocrinol. 1969;61:432–440.
    1. Cumming P., Ase A., Diksic M., Harrison J., Jolly D., Kuwabara H., Laliberté C., Gjedde A. Biochem. Pharmacol. 1995;50:943–946.
    1. Thorne R. G., Pronk G. J., Padmanabhan V., Frey 2nd W. H. Neuroscience. 2004;127:481–496.
    1. Alcala-Barraza S. R., Lee M. S., Hanson L. R., McDonald A. A., Frey, 2nd W. H., McLoon L. K. J. Drug Targeting. 2010;18:179–190.

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