Department of Chemistry, University of Western Ontario, 1151 Richmond Street, London, Ontario, N6A 3 K7, Canada.
London Regional Cancer Program, Lawson Health Research Institute, 800 Commissioners Road East, London, Ontario, N6A 4L6, Canada.
Org Biomol Chem. 2021 Oct 20;19(40):8812-8820. doi: 10.1039/d1ob01023a.
The growth hormone secretagogue receptor 1a (GHSR) is differentially expressed in various disease states compared to healthy tissues and thus is a target for molecular imaging. The endogenous ligand for the GHSR is ghrelin, a 28 amino acid peptide with a unique octanoyl group on the serine-3 residue. A recently reported ghrelin analogue revealed the successful use of fluorine-containing, polycyclic aromatic groups in place of the octanoyl side chain, thereby providing potential access to new F-PET imaging probes. The peptide [Inp,Dpr(6-FN),1Nal,Thr]ghrelin(1-8) amide (1) showed sub-nanomolar receptor affinity (IC = 0.11 nM) toward the GHSR making it the strongest affinity ghrelin analogue reported to date. However, attempts to label such non-activated aromatic groups with fluoride-18 through conventional substitution methods resulted in low radiochemical yields, impractical for use . Since larger, non-activated aromatic groups appear to be of value for incorporating fluorine into ghrelin(1-8) analogues, an additional peptide bearing a 4'-fluorobiphenyl-4-carboxyl (4'-FBC) group in place of the octanoyl side chain was also of interest. Herein, we describe the radiosynthesis of [Inp,Dpr([F]6-FN),1Nal,Thr]ghrelin(1-8) amide ([18F]1) and [Inp,Dpr([F]4'-FBC),1Nal,Thr]ghrelin(1-8) amide ([18F]2) using a prosthetic group approach from iodonium ylide precursors as well as initial and evaluation of [18F]1 as a potential PET tracer for targeted imaging of the GHSR.
生长激素促分泌素受体 1a（GHSR）在与健康组织相比的各种疾病状态下表达不同，因此是分子成像的靶标。GHSR 的内源性配体是 ghrelin，一种 28 个氨基酸的肽，在丝氨酸-3 残基上具有独特的辛酰基。最近报道的一种 ghrelin 类似物揭示了在取代辛酰侧链时使用含氟、多环芳基的成功，从而为新的 F-PET 成像探针提供了潜在途径。肽[Inp，Dpr（6-FN），1Nal，Thr]ghrelin（1-8）酰胺（1）对 GHSR 的受体亲和力为亚纳摩尔级（IC = 0.11 nM），是迄今为止报道的最强亲和力 ghrelin 类似物。然而，通过常规取代方法尝试用氟-18 标记这些非活化的芳基基团导致放射化学产率低，不实用。由于较大的、非活化的芳基基团似乎对于将氟掺入 ghrelin（1-8）类似物中很有价值，因此还对带有 4'-氟联苯-4-羧酸基（4'-FBC）基团代替辛酰侧链的另一种肽也感兴趣。在此，我们描述了使用碘翁叶立德前体作为前体的[Inp，Dpr（[F]6-FN），1Nal，Thr]ghrelin（1-8）酰胺（[18F]1）和[Inp，Dpr（[F]4'-FBC），1Nal，Thr]ghrelin（1-8）酰胺（[18F]2）的放射性合成，以及[18F]1作为 GHSR 靶向成像潜在 PET 示踪剂的初步[18F]1和[18F]2评价。
