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Radionuclide imaging using radiolabeled inhibitors of prostate-specific membrane antigen (PSMA) can be used for the staging of prostate cancer. Previously, we optimized the Glu-urea-Lys binding moiety using a linker structure containing 2-napththyl-L-alanine and L-tyrosine. We have now designed a molecule that contains mercaptoacetyl–triglutamate chelator for labeling with Tc-99m (designated as BQ0413). The purpose of this study was to evaluate the imaging properties of [99mTc]Tc-BQ0413. PSMA-transfected PC3-pip cells were used to evaluate the specificity and affinity of [99mTc]Tc-BQ0413 binding in vitro. PC3-pip tumor-bearing BALB/C nu/nu mice were used as an in vivo model. [99mTc]Tc-BQ0413 bound specifically to PC3-pip cells with an affinity of 33 ± 15 pM. In tumor-bearing mice, the tumor uptake of [99mTc]Tc-BQ0413 (38 ± 6 %IA/g in PC3-pip 3 h after the injection of 40 pmol) was dependent on PSMA expression (3 ± 2 %IA/g and 0.9 ± 0.3 %IA/g in PSMA-negative PC-3 and SKOV-3 tumors, respectively). We show that both unlabeled BQ0413 and the commonly used binder PSMA-11 enable the blocking of [99mTc]Tc-BQ0413 uptake in normal PSMA-expressing tissues without blocking the uptake in tumors. This resulted in an appreciable increase in tumor-to-organ ratios. At the same injected mass (5 nmol), the use of BQ0413 was more efficient in suppressing renal uptake than the use of PSMA-11. In conclusion, [99mTc]Tc-BQ0413 is a promising probe for the visualization of PSMA-positive lesions using single-photon emission computed tomography (SPECT). [ABSTRACT FROM AUTHOR]

Introduction: Prostate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlier, we optimized a urea-based probe for radionuclide visualization of PSMAexpression in vivo using computer modeling. With the purpose to develop a targeting agent equally suitable for radionuclide imaging and therapy, the agent containing DOTA chelator was designed (BQ7876). The aim of the study was to test the hypothesis that 177Lu-labeled BQ7876 possesses target binding and biodistribution properties potentially enabling its use for radiotherapy. Methods: BQ7876 was synthesized and labeled with Lu-177. Specificity and affinity of [177Lu]Lu-BQ7876 to PSMA-expressing PC3-pip cells was evaluated and its processing after binding to cells was studied. Animal studies in mice were performed to assess its biodistribution in vivo, target specificity and dosimetry. [177Lu]Lu-PSMA-617 was simultaneously evaluated for comparison. Results: BQ7876 was labeled with Lu-177 with radiochemical yield >99%. Its binding to PSMA was specific in vitro and in vivo when tested in antigen saturation conditions as well as in PSMA-negative PC-3 tumors. The binding of [177Lu]Lu-BQ7876 to living cells was characterized by rapid association, while the dissociation included a rapid and a slow phase with affinities KD1 = 3.8 nM and KD2 = 25 nM. The half-maximal inhibitory concentration for natLu-BQ7876 was 59 nM that is equal to 61 nM for natLu-PSMA-617. Cellular processing of [177Lu]Lu-BQ7876 was accompanied by slow internalization. [177Lu]Lu-BQ7876 was cleared from blood and normal tissues rapidly. Initial elevated uptake in kidneys decreased rapidly, and by 3 h post injection, the renal uptake (13 ± 3% Frontiers in ID/g) did not differ significantly from tumor uptake (9 ± 3%ID/g). Tumor uptake was stable between 1 and 3 h followed by a slow decline. The highest absorbed dose was in kidneys, followed by organs and tissues in abdomen. Discussion: Biodistribution studies in mice demonstrated that targeting properties of [177Lu]Lu-BQ7876 are not inferior to properties of [177Lu]Lu-PSMA-617, but do not offer any decisive advantages. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer continues to be the most frequently diagnosed form of cancer and the leading cause of cancer-related deaths among men. For a successful treatment plan and outcome, an early diagnosis, correct staging, and monitoring of treatment response are crucial. To improve this, a radiotracer could be used to target the two most abundant proteins overexpressed in prostate cancer: prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR). To date, no such heterodimeric radiotracer is used in the clinic. In this study, we have preclinically characterized and evaluated a galium-68 labelled PSMA/GRPR-targeting radiotracer for PET imaging of prostate cancer. We hope that the findings from this study will be able to contribute to designing better heterodimeric ligands, promote clinical translation of a heterodimer, and serve as a step towards a first-in-human study. The development of radioligands targeting prostate-specific membrane antigen (PSMA) and gastrin-releasing peptide receptor (GRPR) has shown promising results for the imaging and therapy of prostate cancer. However, studies have shown that tumors and metastases can express such targets heterogeneously. To overcome this issue and to improve protein binding, radioligands with the ability to bind both PSMA and GRPR have been developed. Herein, we present the preclinical characterization of [68Ga]Ga-BQ7812; a PSMA/GRPR-targeting radioligand for the diagnostic PET imaging of prostate cancer. This study aimed to evaluate [68Ga]Ga-BQ7812 to promote the translation of such imaging probes into the clinic. [68Ga]Ga-BQ7812 demonstrated rapid and specific binding to both targets in a PSMA/GRPR-expressing PC3-pip cell line. Results from the biodistribution study in PC3-pip xenografted mice showed specific binding to both targets, with the highest activity uptake at 1 h pi in tumor (PSMA+/GRPR+, 10.4 ± 1.0% IA/g), kidneys (PSMA+, 45 ± 16% IA/g), and pancreas (GRPR+, 5.6 ± 0.7% IA/g). At 3h pi, increased tumour-to-organ ratios could be seen due to higher retention in the tumor compared with other PSMA or GRPR-expressing organs. These results, together with low toxicity and an acceptable estimated dosimetry profile (total effective dose = 0.0083 mSv/MBq), support the clinical translation of [68Ga]Ga-BQ7812 and represent a step towards its first clinical trial. [ABSTRACT FROM AUTHOR]

Gastrin releasing peptide receptor (GRPR) is overexpressed in prostate cancer (PC-3) and can be used for diagnostic purposes. We herein present the design and preclinical evaluation of two novel NOTA/NODAGA-containing peptides suitable for labeling with the positron emission tomography (PET) radionuclide Ga-68. These analogs are based on the previously reported GRPR-antagonist DOTAGA-PEG2-[Sar 11 ]RM26, developed for targeted radiotheraostic applications. Both NOTA-PEG2-[Sar 11 ]RM26 and NODAGA-PEG2-[Sar 11 ]RM26 were successfully labeled with Ga-68 and evaluated in vitro and in vivo using PC-3 cell models. Both, [ 68 Ga]Ga-NOTA-PEG2-[Sar 11 ]RM26 and [ 68 Ga]Ga-NODAGA-PEG2-[Sar 11 ]RM26 displayed high metal-chelate stability in phosphate buffered saline and against the EDTA-challenge. The two [ 68 Ga]Ga-labeled conjugates demonstrated highly GRPR-mediated uptake in vitro and in vivo and exhibited a slow internalization over time, typical for radioantagonistis. The [ nat Ga]Ga-loaded peptides displayed affinity in the low nanomole range for GRPR in competition binding experiments. The new radiotracers demonstrated biodistribution profiles suitable for diagnostic imaging shortly after administration with fast background clearance. Their high tumor uptake (13 ± 1 and 15 ± 3% IA/g for NOTA and NODAGA conjugates, respectively) and high tumor-to-blood ratios (60 ± 10 and 220 ± 70, respectively) 3 h pi renders them promising PET tracers for use in patients. Tumor-to-normal organ ratios were higher for [ 68 Ga]Ga-NODAGA-PEG2-[Sar 11 ]RM26 than for the NOTA-containing counterpart. The performance of the two radiopeptides was further supported with the PET/CT images. In conclusion, [ 68 Ga]Ga-NODAGA-PEG2-[Sar 11 ]RM26 is a promising PET imaging tracer for visualization of GRPR-expressing lesions with high imaging contrast shortly after administration., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The feasibility of targeted imaging and therapy using radiolabeled albumin‑binding domain‑derived affinity proteins (ADAPTs) has been demonstrated. However, high renal uptake of radioactivity limits the maximum tolerated dose. Successful reduction of renal retention of radiolabeled Fab fragments has been demonstrated by incorporating a cleavable linker between the targeting agent and the radiometal chelator. The present study investigated if the introduction of a glycine‑leucine‑glycine‑lysine (GLGK)‑linker would reduce the kidney uptake of radiolabeled ADAPT6 and also compared it with the non‑residualizing [ 125 I]I‑[(4‑hydroxyphenyl)ethyl]maleimide ([ 125 I]I‑HPEM) labeling strategy. GLGK was site‑specifically coupled to human epidermal growth factor receptor 2 (HER2)‑targeting ADAPT6. Conjugates without the cleavable linker were used as controls and all constructs were labeled with lutetium‑177 ( 177 Lu). [ 125 I]I‑HPEM was coupled to ADAPT6 at the C‑terminus. Biodistribution of all constructs was evaluated in NMRI mice 4 h after injection. Specific binding to HER2‑expressing cells in vitro was demonstrated for all constructs. No significant difference in kidney uptake was observed between the [ 177 Lu]Lu‑2,2',2",2"'‑(1,4,7,10‑tetraazacyclododecane‑1,4,7,10‑tetrayl)tetraacetic acid‑GLGK‑conjugates and the controls. The renal activity of [ 125 I]I‑HPEM‑ADAPT6 was significantly lower compared with all other constructs. In conclusion, the incorporation of the cleavable GLGK‑linker did not result in lower renal retention. Therefore, the present study emphasized that, in order to achieve a reduction of renal retention, alternative molecular design strategies may be required for different targeting agents.

Introduction: Prostate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlier, we optimized a urea-based probe for radionuclide visualization of PSMA-expression in vivo using computer modeling. With the purpose to develop a targeting agent equally suitable for radionuclide imaging and therapy, the agent containing DOTA chelator was designed (BQ7876). The aim of the study was to test the hypothesis that 177 Lu-labeled BQ7876 possesses target binding and biodistribution properties potentially enabling its use for radiotherapy., Methods: BQ7876 was synthesized and labeled with Lu-177. Specificity and affinity of [ 177 Lu]Lu-BQ7876 to PSMA-expressing PC3-pip cells was evaluated and its processing after binding to cells was studied. Animal studies in mice were performed to assess its biodistribution in vivo , target specificity and dosimetry. [ 177 Lu]Lu-PSMA-617 was simultaneously evaluated for comparison., Results: BQ7876 was labeled with Lu-177 with radiochemical yield >99%. Its binding to PSMA was specific in vitro and in vivo when tested in antigen saturation conditions as well as in PSMA-negative PC-3 tumors. The binding of [ 177 Lu]Lu-BQ7876 to living cells was characterized by rapid association, while the dissociation included a rapid and a slow phase with affinities K D1 = 3.8 nM and K D2 = 25 nM. The half-maximal inhibitory concentration for nat Lu-BQ7876 was 59 nM that is equal to 61 nM for nat Lu-PSMA-617. Cellular processing of [ 177 Lu]Lu-BQ7876 was accompanied by slow internalization. [ 177 Lu]Lu-BQ7876 was cleared from blood and normal tissues rapidly. Initial elevated uptake in kidneys decreased rapidly, and by 3 h post injection, the renal uptake (13 ± 3%ID/g) did not differ significantly from tumor uptake (9 ± 3%ID/g). Tumor uptake was stable between 1 and 3 h followed by a slow decline. The highest absorbed dose was in kidneys, followed by organs and tissues in abdomen., Discussion: Biodistribution studies in mice demonstrated that targeting properties of [ 177 Lu]Lu-BQ7876 are not inferior to properties of [ 177 Lu]Lu-PSMA-617, but do not offer any decisive advantages., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Abouzayed, Seitova, Lundmark, Bodenko, Oroujeni, Tolmachev, Rosenström and Orlova.)