The 18-membered macrocycle H macropa was investigated for Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all Ac (26 kBq) in 5 min at RT. [ Ac(macropa)] remained intact over 7 to 8 days when challenged with either excess La ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled Ac in just minutes at RT, and macropa-Tmab retained>99 % of its Ac in human serum after 7 days. In LNCaP xenograft mice, Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free Ac over 96 h. These findings establish macropa to be a highly promising ligand for Ac chelation that will facilitate the clinical development of Ac TAT for the treatment of soft-tissue metastases.
The high tumor uptake achieved with these trifunctional ligands predicts larger (up to 4×) doses delivered to the tumor than can be achieved with Lu-PSMA-617. Although PSMA-mediated kidney uptake was also observed, the exceptional area under the curve (AUC) in the tumor warrants further investigation of these novel ligands as candidates for RLT.
Prostate-specific membrane antigen (PSMA)-targeted radiotherapy of prostate cancer (PCa) has emerged recently as a promising approach to the treatment of disseminated disease. A small number of ligands have been evaluated in patients, and although early tumor response is encouraging, relapse rate is high and these compounds localize to the parotid, salivary, and lacrimal glands as well as to the kidney, leading to dose-limiting toxicities and adverse events affecting quality of life. We envision that dual-target binding ligands displaying high affinity for PSMA and appropriate affinity for human serum albumin (HSA) may demonstrate a higher therapeutic index and be suitable for treatment of PCa by targeted α-therapy. Six novel urea-based ligands with varying affinities for PSMA and HSA were synthesized, labeled withI, and evaluated by in vitro binding and uptake assays in LNCaP cells. Four compounds were advanced for further evaluation in a preclinical model of PCa. The compounds were compared with MIP-1095, a PSMA ligand currently in clinical evaluation. The compounds demonstrated affinity for PSMA on the order of 4-40 nM and affinity for HSA in the range of 1-53 μM. Compounds with relatively high affinity for HSA (≤2 μM) showed high and sustained blood-pool activity and reduced uptake in the kidneys.I-RPS-027, with a 50% inhibitory concentration (PSMA) of 15 nM and a dissociation constant (HSA) of 11.2 μM, cleared from the blood over the course of 48 h and showed good tumor uptake (10 percentage injected dose per gram) and retention and a greater than 5-fold decrease in kidney uptake relative to MIP-1095. The tumor-to-kidney ratio of I-RPS-027 was greater than 3:1 at 24 h after injection, increasing to 7:1 by 72 h. RPS-027 shows dual targeting to PSMA and albumin, resulting in a high tumor uptake, highly favorable tissue distribution, and promising therapeutic profile in a preclinical model of prostate cancer. In comparison to existing ligands proposed for targeted therapy of prostate cancer, RPS-027 has tumor-to-tissue ratios that predict a significant reduction in side effects during therapy. Using iodine/radioiodine as a surrogate for the radiohalogen At, we therefore propose dual-target binding ligands such as RPS-027 as next-generation radiopharmaceuticals for targeted α-therapy usingAt.
Promising biochemical responses to 225 Ac-prostate-specific membrane antigen (PSMA) 617, even in patients who are refractory to βparticle radiation, illustrate the potential of targeted α-therapy for the treatment of metastatic castration-resistant prostate cancer. However, side effects such as xerostomia are severe and irreversible. To fully harness the potential of targeted α-therapy, it is necessary to increase the therapeutic index of the targeted radioligands. One emerging strategy is to increase clearance half-life through enhanced binding to serum albumin. We have evaluated the albumin-binding PSMA-targeting ligand RPS-074 in a LNCaP xenograft model to determine its potential value to the treatment of prostate cancer. Methods: 225 Ac-RPS-074 was evaluated in male BALB/c mice bearing LNCaP xenograft tumors. A biodistribution study was performed over 21 d to determine the dosimetry in tumors and normal tissue. The dose response was measured in groups of 7 mice using 37, 74, and 148 kBq of 225 Ac-RPS-074 and compared with positive and negative control groups. Mice were sacrificed when tumor volume exceeded 1,500 mm 3 . Results: 225 Ac-RPS-074 was labeled in greater than 98% radiochemical yield and showed high (.10% injected dose/g) and sustained accumulation in LNCaP tumors from 24 h to beyond 14 d. Signal in blood and highly vascularized tissues was evident over the first 24 h after injection and cleared by 7 d. The tumor-tokidney ratio was 4.3 ± 0.7 at 24 h and 62.2 ± 9.5 at 14 d. A single injection of 148 kBq induced a complete response in 6 of 7 tumors, with no apparent toxic effects. Treatment with 74 kBq induced a partial response in 7 of 7 tumors, but from 42 d, 6 of 7 experienced significant regrowth. The 37-kBq group experienced a survival benefit relative to the negative control but not compared with the positive control group. Conclusion: A single dose of 148 kBq of 225 Ac-RPS-074 induced a complete response in 86% of tumors, with tumor-to-normal-tissue ratios that predict an improved therapeutic index. The use of the macropa chelator enabled quantitative radiolabeling and may facilitate the clinical translation of this promising targeted α-therapeutic. Ac-RPS-074 Induces a Complete Tumor Response in an LNCaP 225 A Single Dose of http://jnm.snmjournals.org/content/60/5/649 This article and updated information are available at: http://jnm.snmjournals.org/site/subscriptions/online.xhtml Information about subscriptions to JNM can be found at: http://jnm.snmjournals.org/site/misc/permission.xhtml
The 18-membered macrocycle H 2 macropa was investigated for 225 Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225 Ac (26 kBq) in 5min at RT.[ 225 Ac(macropa)] + remained intact over 7t o 8dayswhen challenged with either excess La 3+ ions or human serum, and did not accumulate in any organ after 5hin healthy mice.Abifunctional analogue,macropa-NCS,was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled 225 Ac in just minutes at RT,a nd macropa-Tmab retained > 99 %o fi ts 225 Ac in human serum after 7days. In LNCaP xenograft mice, 225 Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225 Ac over 96 h. These findings establish macropa to be ah ighly promising ligand for 225 Ac chelation that will facilitate the clinical development of 225 Ac TATf or the treatment of soft-tissue metastases.Radium-223 ( 223 Ra) is the first therapeutic a-emitting radionuclide to be approved for clinical use in cancer patients. Administered as 223 RaCl 2 ,i th as been employed in the treatment of metastatic castration-resistant prostate cancer since 2013. [1] Theo steophilic nature and high-energy aparticle emanations,respectively,of 223 Ra 2+ ions are effective for targeting and eradicating bone metastases originating from this disease. [2] To more generally harness the therapeutic potential of a-particles for soft-tissue metastases,the strategy of targeted alpha-particle therapy (TAT)h as emerged, [3,4] whereby lethal a-emitting radionuclides are conjugated to tumor-targeting vectors using bifunctional chelators [5] to selectively deliver cytotoxic a radiation to cancer cells (Figure 1a).Among the suitable radionuclides for such an application, actinium-225 ( 225 Ac) is highly promising for use in TATowing to its long 10-day half-life that is compatible with antibodybased targeting vectors and four high-energy a-emissions that are extremely lethal to cells. [6][7][8][9][10] Ak ey challenge for the implementation of 225 Ac TATi st he lack of as uitable bifunctional chelator that can rapidly bind the Ac 3+ ion and stably retain it in vivo. [11][12][13][14] Although ah ighly promising bispidine-based chelator has recently been disclosed, [15] the 12-membered tetraaza macrocycle H 4 DOTA (Figure 1b)i s currently the state of the art for the chelation of the 225 Ac 3+ ion. [7,12,16] However,t he thermodynamic stabilities of complexes of H 4 DOTA decrease as the ionic radius of the metal ion increases, [17,18] thus indicating that this ligand is not optimal for chelation of the Ac 3+ ion, the largest + 3ion in the periodic table. [19] Furthermore,the 225 Ac-radiolabeling kinetics of this ligand are slow (see below), thus necessitating the Figure 1. a) Schematic diagram depicting the concept of targeted alpha therapy using 225 Ac. b) Structures of the ligands discussedi n this work. Supportinginformation and the ORCID identification n...
Despite significant gains in the treatment of metastatic castrationresistant prostate cancer by radioligands targeting prostate-specific membrane antigen (PSMA), 30% of patients never respond to therapy. One possible explanation is insufficient dose delivery to the tumor because of suboptimal pharmacokinetics. We have recently described RPS-063, a trifunctional ligand targeting PSMA with high uptake in LNCaP xenograft tumors but also in kidneys. We aimed to use structural modifications to increase the tumor-to-kidney ratio through increased albumin binding and tumor uptake and reduction of kidney activity. Methods: Four structurally related trifunctional PSMA-targeting small molecules were prepared by either varying the albumin-binding group or inserting a polyethylene glycol 8 linker into a common structure. The compounds were ranked by PSMA affinity and albumin affinity and were radiolabeled with 68 Ga and 177 Lu. Tissue kinetics were determined in male BALB/C nu/nu mice bearing LNCaP xenograft tumors. Results: Each of the compounds binds PSMA with a half-maximal inhibitory concentration of no more than 10 nM. The albumin-binding group had a minimal effect on PSMA affinity but changed albumin affinity by an order of magnitude. However, the addition of a polyethylene glycol 8 spacer weakened affinity for albumin in each case. Increased affinity for albumin corresponded with delayed blood clearance and modified uptake kinetics in the tumor and kidney. Uptake of 177 Lu-RPS-072 (34.9 ± 2.4 %ID/g) and 177 Lu-RPS-077 (27.4 ± 0.6 %ID/g) increased up to 24 h after injection, and washout by 96 h was not significant. As a result, the area under the curve (AUC) in the tumor was in the following order: 177 Lu-RPS-072 . 177 Lu-RPS-077 . 177 Lu-RPS-063 . 177 Lu-RPS-071. Increased linker length corresponded to more rapid clearance from kidneys. Consequently, the ratio of tumor AUC and kidney AUC was 4.7 ± 0.3 for 177 Lu-RPS-072. Conclusion: The tumor AUC and tumor-to-kidney ratio of 177 Lu-RPS-072 are significantly enhanced compared with any small molecule investigated in a LNCaP xenograft model to date. In comparison to other PSMAtargeting radioligands that have been evaluated in a PC3-PIP model, activity in kidneys is reduced and activity in tumors compares favorably when the different PSMA expression levels in LNCaP and PC3-PIP cells are considered. RPS-072 therefore exhibits an increased therapeutic index, shows the potential to increase the dose delivered to tumors, and is a highly promising candidate for targeted radioligand therapy.
PurposeCurrent clinical imaging of PSMA-positive prostate cancer by positron emission tomography (PET) mainly features 68Ga-labeled tracers, notably [68Ga]Ga-PSMA-HBED-CC. The longer half-life of fluorine-18 offers significant advantages over Ga-68, clinically and logistically. We aimed to develop high-affinity PSMA inhibitors labeled with fluorine-18 as alternative tracers for prostate cancer.MethodsSix triazolylphenyl ureas and their alkyne precursors were synthesized from the Glu-urea-Lys PSMA binding moiety. PSMA affinity was determined in a competitive binding assay using LNCaP cells. The [18F]triazoles were isolated following a Cu(I)-catalyzed click reaction between the alkynes and [18F]fluoroethylazide. The 18F-labeled compounds were evaluated in nude mice bearing LNCaP tumors and compared to [68Ga]Ga-PSMA-HBED-CC and [18F]DCFPyL. Biodistribution studies of the two tracers with the highest imaged-derived tumor uptake and highest PSMA affinity were undertaken at 1 h, 2 h and 4 h post-injection (p.i.), and co-administration of PMPA was used to determine whether uptake was PSMA-specific.ResultsF-18-labeled triazolylphenyl ureas were prepared with a decay-corrected RCY of 20–40 %, >98 % radiochemical and chemical purity, and specific activity of up to 391 GBq/μmol. PSMA binding (IC50) ranged from 3–36 nM. The position of the triazole influenced tumor uptake (3 > 4 > 2), and direct conjugation of the triazole with the phenylurea moiety was preferred to insertion of a spacer group. Image-derived tumor uptake ranged from 6–14 %ID/g at 2 h p.i., the time of maximum tumor uptake; uptake of [68Ga]Ga-PSMA-HBED-CC and [18F]DCFPyL was 5–6 %ID/g at 1–3 h p.i., the time of maximum tumor uptake. Biodistribution studies of the two most promising compounds gave maximum tumor uptakes of 10.9 ± 1.0 % and 14.3 ± 2.5 %ID/g, respectively, as compared to 6.27 ± 1.44 %ID/g for [68Ga]Ga-PSMA-HBED-CC.ConclusionsSix [18F]triazolylphenyl ureas were prepared in good radiochemical yield. Compounds showed PSMA-specific uptake in LNCaP tumors as high as 14 % ID/g, more than a 2-fold increase over [68Ga]Ga-PSMA-HBED-CC. The facile and high-yielding radiosynthesis of these 18F-labeled triazoles as well as their promising in vitro and in vivo characteristics make them worthy of clinical development for PET imaging of prostate cancer.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-016-3556-5) contains supplementary material, which is available to authorized users.
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