pharmaceutics Review The Significance of NK1 Receptor Ligands and Their Application in Targeted Radionuclide Tumour Therapy Agnieszka Majkowska-Pilip * , Paweł Krzysztof Halik and Ewa Gniazdowska Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland * Correspondence: [email protected]; Tel.: +48-22-504-10-11 Received: 7 June 2019; Accepted: 16 August 2019; Published: 1 September 2019 Abstract: To date, our understanding of the Substance P (SP) and neurokinin 1 receptor (NK1R) system shows intricate relations between human physiology and disease occurrence or progression. Within the oncological field, overexpression of NK1R and this SP/NK1R system have been implicated in cancer cell progression and poor overall prognosis. This review focuses on providing an update on the current state of knowledge around the wide spectrum of NK1R ligands and applications of radioligands as radiopharmaceuticals. In this review, data concerning both the chemical and biological aspects of peptide and nonpeptide ligands as agonists or antagonists in classical and nuclear medicine, are presented and discussed. However, the research presented here is primarily focused on NK1R nonpeptide antagonistic ligands and the potential application of SP/NK1R system in targeted radionuclide tumour therapy. Keywords: neurokinin 1 receptor; Substance P; SP analogues; NK1R antagonists; targeted therapy; radioligands; tumour therapy; PET imaging 1. Introduction Neurokinin 1 receptor (NK1R), also known as tachykinin receptor 1 (TACR1), belongs to the tachykinin receptor subfamily of G protein-coupled receptors (GPCRs), also called seven-transmembrane domain receptors (Figure1)[ 1–3]. The human NK1 receptor structure [4] is available in Protein Data Bank (6E59). Tachykinins, widely distributed within the central (CNS) and peripheral (PNS) nervous system, are small bioactive neuropeptides which share a conserved C-terminal pentapeptide sequence, Phe-X-Gly-Leu-Met-NH2. Examples of these neurotransmitters belonging to the tachykinin group include Substance P (SP), the first neuropeptide discovered in mammals [5], neurokinin A (NKA) and neurokinin B (NKB). These compounds listed above are the preferential ligands for NK1, NK2 and NK3 receptors, respectively, although they can bind additional NK receptors with varying affinity [6]. Pharmaceutics 2019, 11, 443; doi:10.3390/pharmaceutics11090443 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2019, 11, 443 2 of 28 Pharmaceutics 2019, 11, x FOR PEER REVIEW 2 of 29 Figure 1. SchematicSchematic model model of of NK1 NK1 receptor of full length isoform (NK1R-Fl) [[3].3]. Within thethe neurokinin neurokinin receptor receptor family, family, there there are three are pharmacologicallythree pharmacologically distinct receptordistinct subtypes:receptor subtypes:NK1R (TACR1, NK1R SPR),(TACR1, NK2R SPR), (TACR2) NK2R (TACR2) and NK3R and (TACR3) NK3R (TACR3) [7–9]. NK1R [7–9]. is NK1R widely is expressedwidely expressed in both inthe both CNS the and CNS PNS, and whereas PNS, whereas NK2R isNK2R preferentially is preferentially expressed expressed in PNS in [9 ].PNS NK1R [9]. containsNK1R contains 407 amino 407 aminoacids, andacids, NK2R and NK2R and NK3R and NK3R (the longest (the longest one) consistone) consist of 398 of and398 and 465 amino465 amino acids, acids, respectively respectively [3]. [3].NK1R NK1R exists exists in two in isoforms,two isoforms, as a full-length as a full-length peptide peptide (NK1R-Fl, (NK1R-Fl, Figure 1Figure) and in 1) the and truncated in the truncated isoform (NK1R-Tr),isoform (NK1R-Tr), containing containing 311 amino 311 acids amino (96 amino acids acids(96 amino less at acids the C-terminus) less at the C-terminus) [3]. NK1R displays [3]. NK1R two displaysnonstoichiometric two nonstoichiometric binding sites, bi thending more sites, abundant the more NK-1M abundant (“majority”—representing NK-1M (“majority”—representing 80–85% of the 80–85%total receptor of the population) total receptor and NK-1mpopulation) (“minority”—so-called and NK-1m (“minority”—so-called “septide sites” or “septide-sensitive”)“septide sites” or “septide-sensitive”)defined according to defined the different according binding to potenciesthe different of SPbinding and its potencies analogues of [ 10SP– and14]. its NK1R analogues contains [10– an 14].extracellular NK1R contains N-terminus, an extracellular three extracellular N-terminus, loops three (E1, E2extracellular and E3), seven loops transmembrane (E1, E2 and E3), domains, seven transmembranethree intracellular domains, loops (C1, three C2 andintracellular C3, as well loops as a (C1, possible C2 and C4 C3, loop) as andwell an as intracellulara possible C4 C-terminus. loop) and an intracellularThe wide overexpression C-terminus. of NK1R in various human organs has led to successful development of highlyThe wide selective overexpression agonists and of antagonists NK1R in various of this human receptor organs for the has treatment led to successful of various development diseases [8]. ofSome highly NK1R selective ligands, agonists for example and antagonists SP, its analogues of this and receptor derivatives, for the have treatment been investigated of various indiseases preclinical [8]. Someand clinical NK1R studies. ligands, Moreover, for example based SP, on highits analogues density of transmembraneand derivatives, NK1Rs have onbeen human investigated cancer cells, in preclinicalnew therapeutic and clinical approaches studies. involve Moreover, the use based of radiolabelledon high density NK1R of transmembrane ligands in targeted NK1Rs radionuclide on human cancertumour cells, therapy new [ 2therapeutic,15–17]. approaches involve the use of radiolabelled NK1R ligands in targeted radionuclideThe aim tumour of this reviewtherapy is[2,15–17]. to discuss data from recent literature concerning the chemical and biologicalThe aim aspects of this of naturalreview is and to syntheticdiscuss data NK1R from ligands recent in literature classical andconcerning nuclear the medicine, chemical with and a biologicalspecific focus aspects on targeted of natural radionuclide and synthetic therapy. NK1R ligands in classical and nuclear medicine, with a specific focus on targeted radionuclide therapy. 2. NK1R Ligands in Classical Medicine 2. NK1R Ligands in Classical Medicine 2.1. Significance of NK1R Agonists 2.1. SignificanceThe endogenous of NK1R peptide Agonists ligands of NK1R are tachykinins, a large family of neuropeptides produced by neuronal and glial cells [5,18]. These compounds play an important role in nociception, The endogenous peptide ligands of NK1R are tachykinins, a large family of neuropeptides synaptic transmission (as excitatory neurotransmitters) and neuroimmunomodulation. They have a produced by neuronal and glial cells [5,18]. These compounds play an important role in nociception, variety of effects on physiological and pathological conditions, as well as intrinsic neuroprotective and synaptic transmission (as excitatory neurotransmitters) and neuroimmunomodulation. They have a neurodegenerative properties [19]. The tachykinin family is characterized by a common C-terminal variety of effects on physiological and pathological conditions, as well as intrinsic neuroprotective 5-amino-acid sequence Phe-X-Gly-Leu-Met-NH , where X is either an aromatic (Phe or Tyr) or a and neurodegenerative properties [19]. The tach2 ykinin family is characterized by a common C- branched chain aliphatic (Val or Ile) amino acid residue [19–21]. terminal 5-amino-acid sequence Phe-X-Gly-Leu-Met-NH2, where X is either an aromatic (Phe or Tyr) The most widespread and tested agonistic peptide ligand of NK1R is human endogenous or a branched chain aliphatic (Val or Ile) amino acid residue [19–21]. undecaneuropeptide Substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH , SP(1–11), SP, The most widespread and tested agonistic peptide ligand of NK1R is human2 endogenous [Arg1]SP, Figure2). At physiological pH, SP characteristically holds a positive charge on N-terminal undecaneuropeptide Substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2, SP(1–11), amino acid residues. The C-terminus contains hydrophobic residues providing the SP peptide with SP, [Arg1]SP, Figure 2). At physiological pH, SP characteristically holds a positive charge on N- terminal amino acid residues. The C-terminus contains hydrophobic residues providing the SP peptide with an amphiphilic character [22]. The interaction between SP and NK1R results in Pharmaceutics 2019, 11, 443 3 of 28 Pharmaceutics 2019, 11, x FOR PEER REVIEW 3 of 29 an amphiphilic character [22]. The interaction between SP and NK1R results in internalisation of the membrane-boundinternalisation of complex,the membrane-bound via a clathrin-dependent complex, via mechanism, a clathrin-dependent to the acidified mechanism, endosomes, to where the theacidified complex endosomes, disassociates where [8, 22the– 24complex]. disassociates [8,22–24]. H2N H2N O O O O H H N N N H2N N H N N O O H O O NH H N H2N O O O NH O H HN N NH N 2 O H2N S Figure 2. Structure of Substance P(1–11). The SP SP fragment fragment responsible responsible for NK1R for affinity NK1R is a ffia nityfive amino is a acid five sequence, amino Phe acid7–Phe sequence,8–Gly9– 7 8 9 10 11 PheLeu10–Phe–Met11–Gly, located–Leu at the–Met C-terminus, located of at the the peptide C-terminus [21,25,26]. of the Tachykinins peptide [21 are,25, 26degraded]. Tachykinins by neutral are degradedendopeptidases by