Prototypic ¹⁸F-Labeled Argininamide-Type Neuropeptide Y Y₁R Antagonists as Tracers for PET Imaging of Mammary Carcinoma

Abstract

The neuropeptide Y (NPY) Y receptor (YR) selective radioligand ()--(2,2-diphenylacetyl)--[4-(2-[F]fluoropropanoylamino)butyl]aminocarbonyl--(4-hydroxybenzyl)argininamide (), derived from the high-affinity YR antagonist BIBP3226, was developed for imaging studies of YR-positive tumors. Starting from the argininamide core bearing amine-functionalized spacer moieties, a series of fluoropropanoylated and fluorobenzoylated derivatives was synthesized and studied for YR affinity. The fluoropropanoylated derivative displayed high affinity ( = 1.3 nM) and selectivity toward YR. Radiosynthesis was accomplished via F-fluoropropanoylation, yielding with excellent stability in mice; however, the biodistribution study revealed pronounced hepatobiliary clearance with high accumulation in the gall bladder (>100 %ID/g). Despite the unfavorable biodistribution, was successfully used for imaging of YR positive MCF-7 tumors in nude mice. Therefore, we suggest as a lead for the design of PET ligands with optimized physicochemical properties resulting in more favorable biodistribution and higher YR-dependent enrichment in mammary carcinoma.

Design, synthesis, and biological evaluation of a multifunctional neuropeptide-Y conjugate for selective nuclear delivery of radiolanthanides

“…The difference in affinity between the 111 In-labeled version of pb12 and its nat Tb counterpart illustrates the necessity of carefully determining affinity of metallated compounds for imaging and therapy. Importantly, these nanomolar affinity values compete well with other full-length peptides [17] or non-peptide ligands [21] and are better than those reported for truncated peptides [22].…”

“…Targeted radionuclide therapy holds promise to deliver radiation to tumor cells over-expressing peptide receptors. In this work, we aimed to explore the feasibility of enhanced-TRT by using a subcellular active (radio) pharmaceutical able to deliver Auger-electron emitter like 161 Tb, in tumors over-expressing the hY 1 R. Several strategies have been used to develop NPY ligands for imaging and therapy (non-peptide ligands, antagonistictruncated peptides, or agonistic full-length peptides) with variable success [19,21,22]. The full-length hY 1 Rpreferring peptide analog [F 7 ,P 34 ]-NPY allows selective delivery of cargos such as radioisotopes [12,17,23].…”

Design, Synthesis, In Vitro, and Initial In Vivo Evaluation of Heterobivalent Peptidic Ligands Targeting Both NPY(Y1)- and GRP-Receptors—An Improvement for Breast Cancer Imaging?

“…As it was described that MCF-7 cells can express the target NPY(Y 1 )R to a much higher extent in vivo than under in vitro conditions [ 34 ], this might also be the case for the T-47D cell line, expressing besides the NPY(Y 1 )R also the for our scientific question important GRPR. Thus, we in the following performed initial in vivo evaluations of HBPL [ 68 Ga] 24 , showing highly promising results in the preceding evaluations.…”

Less Exploited GPCRs in Precision Medicine: Targets for Molecular Imaging and Theranostics

“…Such a situation, namely the low number of preclinical or clinical assays reported in the literature [67,68,69,70,71], has been partially ascribed to the in vivo instability of the targeting peptides [72,73,74,75]. Although not as extensively as the peptide receptors mentioned above, neuropeptide Y receptor subtypes 1 (NPYR1) and 2 (NPYR2) have also been studied as imaging targets for NPYR1-expressing tumors such as breast cancer, [76,77,78,79,80,81,82,83,84] and for brain imaging [85], respectively.…”