Synthesis and Evaluation of Ga- and Lu-Labeled [Pro]bombesin(8-14) Derivatives for Detection and Radioligand Therapy of Gastrin-Releasing Peptide Receptor-Expressing Cancer.

The gastrin-releasing peptide receptor (GRPR) is overexpressed in a variety of cancers and represents a promising target for diagnosis and therapy. However, the extremely high accumulation in the pancreas observed for most of the clinically evaluated GRPR-targeted radiopharmaceuticals could limit their applications. In this study, we synthesized one GRPR antagonist (ProBOMB5) and two GRPR agonists (LW02056 and LW02057) by replacing the 4-thiazolidinecarboxylic acid (Thz) residue in our previously reported GRPR-targeted tracers with Pro.

Synthesis and Evaluation of the First Ga-Labeled -Terminal Hydroxamate-Derived Gastrin-Releasing Peptide Receptor-Targeted Tracers for Cancer Imaging with Positron Emission Tomography.

Gastrin-releasing peptide receptor (GRPR), overexpressed in many solid tumors, is a promising imaging marker and therapeutic target. Most reported GRPR-targeted radioligands contain a -terminal amide. Based on the reported potent antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH, we synthesized -terminal hydroxamate-derived [Ga]Ga-LW02075 ([Ga]Ga-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH) and [Ga]Ga-LW02050 ([Ga]Ga-DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHOH), and compared them with the closely related and clinically validated [Ga]Ga-SB3 ([Ga]Ga-DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt).

Synthesis and Evaluation of Novel Ga-Labeled [D-Phe,LeuψThz]bombesin(6-14) Analogs for Cancer Imaging with Positron Emission Tomography.

Gastrin-releasing peptide receptor (GRPR) is overexpressed in various cancers and is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake and/or metabolic instability observed for most reported GRPR-targeted radioligands might limit their clinical applications. Our group recently reported a GRPR-targeted antagonist tracer, [Ga]Ga-TacsBOMB2 ([Ga]Ga-DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-LeuψThz-NH), which showed a minimal pancreas uptake in a preclinical mouse model.

Unnatural amino acid substitutions to improve in vivo stability and tumor uptake of Ga-labeled GRPR-targeted TacBOMB2 derivatives for cancer imaging with positron emission tomography.

Background: Overexpressed in various solid tumors, gastrin-releasing peptide receptor (GRPR) is a promising cancer imaging marker and therapeutic target. Although antagonists are preferable for the development of GRPR-targeted radiopharmaceuticals due to potentially fewer side effects, internalization of agonists may lead to longer tumor retention and better treatment efficacy. In this study, we systematically investigated unnatural amino acid substitutions to improve in vivo stability and tumor uptake of a previously reported GRPR-targeted agonist tracer, [Ga]Ga-TacBOMB2 (Ga-DOTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-Thz-NH).

Synthesis and Evaluation of Tc-Labeled PSMA-Targeted Tracers Based on the Lys-Urea-Aad Pharmacophore for Detecting Prostate Cancer with Single Photon Emission Computed Tomography.

Prostate-specific membrane antigen (PSMA) is a well-validated prostate cancer marker but reported PSMA-targeted tracers derived from the Lys-urea-Glu pharmacophore including the clinically validated [Tc]Tc-EDDA/HYNIC-iPSMA have high off-target uptake in kidneys, spleen, and salivary glands. In this study, we synthesized and evaluated three novel Tc-labeled PSMA-targeted tracers and investigated if the tracers derived from the Lys-urea-Aad pharmacophore could have minimized uptake in off-target organs/tissues. In vitro competition binding assays showed that compared with HYNIC-iPSMA, the three novel ligands had slightly weaker PSMA binding affinity (average K = 3.

Comparative Evaluation of [F]5-Fluoroaminosuberic Acid and (4)-4-3-[F]fluoropropyl)-l-Glutamate as System xC--Targeting Radiopharmaceuticals.

System [Formula: see text] is an appealing biomarker for targeting oxidative stress with oncologic PET imaging and can serve as an alternative PET biomarker to other metabolic indicators. In this paper, we report a direct comparison of 2 F-labeled amino acid radiopharmaceuticals targeting system [Formula: see text], [F]5-fluoroaminosuberic acid ([F]FASu) and (4)-4-(3-[F]fluoropropyl)-l-glutamate ([F]FSPG), in terms of their uptake specificity and ability to image glioma and lung cancer xenografts in vivo. Both tracers were synthesized according to previously published procedures.

Synthesis and Evaluation of Ga-Labeled (2,4)-4-Fluoropyrrolidine-2-Carbonitrile and (4)-Thiazolidine-4-Carbonitrile Derivatives as Novel Fibroblast Activation Protein-Targeted PET Tracers for Cancer Imaging.

Fibroblast activation protein α (FAP-α) is a cell-surface protein overexpressed on cancer-associated fibroblasts that constitute a substantial component of tumor stroma and drive tumorigenesis. FAP is minimally expressed by most healthy tissues, including normal fibroblasts. This makes it a promising pan-cancer diagnostic and therapeutic target.

A Radiotracer for Molecular Imaging and Therapy of Gastrin-Releasing Peptide Receptor-Positive Prostate Cancer.

The gastrin-releasing peptide receptor (GRPR) is overexpressed in many solid malignancies, particularly in prostate and breast cancers, among others. We synthesized ProBOMB2, a novel bombesin derivative radiolabeled with Ga and Lu, and evaluated its ability to target GRPR in a preclinical model of human prostate cancer. ProBOMB2 was synthesized in solid phase using fluorenylmethoxycarbonyl chemistry.

Development and biological evaluation of[F]FMN3PA & [F]FMN3PU for leucine-rich repeat kinase 2 (LRRK2) in vivo PET imaging.

Purpose: Among all genetic mutations of LRRK2, the G2019S mutation is the most commonly associated with the late-onset of Parkinson's disease (PD). Hence, one potential therapeutic approach is to block the hyperactivity of mutated LRRK2 induced by kinase inhibition. To date, only a few LRRK2 kinase inhibitors have been tested for in vivo quantification of target engagement by positron emission tomography (PET).

Angiotensin II type 1 receptor blocker telmisartan inhibits the development of transient hypoxia and improves tumour response to radiation.

Hypoxic tumour cells are radiation-resistant and are associated with poor therapeutic outcome. A poorly understood source of tumour hypoxia is unstable perfusion, which exposes tumour cells to varying oxygen tensions over time creating "transiently" hypoxic cells. Evidence suggests that angiotensin II type 1 receptor blockers (ARBs) can improve tumour perfusion by reducing collagen deposition from cancer associated fibroblasts (CAFs).

Buoctapa-alkyl-NHS for metalloradiopeptide preparation.

The peptide is an important class of biological targeting molecule; herein, a new bifunctional octadentate non-macrocyclic H4octapa, tBu4octapa-alkyl-NHS, which is compatible with solid-phase peptide synthesis and thus useful for radiopeptide preparation, has been synthesized. To preserve denticity, the alkyl-N-hydroxylsuccinimide linker was covalently attached to the methylene-carbon on one of the acetate arms, yielding a chiral carbon center. According to density-functional theory (DFT) calculations using [Lu(octapa-alkyl-benzyl-ester)]- as a simulation model, the chirality has minimal effects on the complex geometry; regardless of the S-/R-stereochemistry, DFT calculations revealed two possible geometric isomers, distorted bicapped trigonal antiprism (DBTA) and distorted square antiprism (DSA), due to the asymmetry in the chelator.

Selective Cyclized α-Melanocyte-Stimulating Hormone Derivative with Multiple -Methylations for Melanoma Imaging with Positron Emission Tomography.

In this study, we designed and evaluated a novel α-melanocyte-stimulating hormone derivative with four -methylations for melanocortin 1 receptor-targeted melanoma imaging with positron emission tomography (PET). The resulting peptide, DOTA-Pip-Nle-Cyclo[Asp--Me-His-d-Phe--Me-Arg--Me-Trp--Me-Lys]αMSH-NH (CCZ01099), showed high receptor selectivity, greatly improved stability, and rapid internalization. [Ga]Ga-CCZ01099 showed clear tumor visualization and excellent tumor-to-normal tissue contrast with PET imaging in a preclinical melanoma model.

The Effect of Chirality on the Application of 5-[F]Fluoro-Aminosuberic Acid ([F]FASu) for Oxidative Stress Imaging.

Purpose: The cystine transporter, system x, plays a crucial role in sustaining redox homeostasis and is reported to be overexpressed in several cancer subtypes. 5-[F]Fluoroaminosuberic acid ([F]FASu) is a novel positron emission tomography (PET) tracer, which exhibits specific uptake via system x. [F]FASu synthesis by the commonly used Kryptofix 2.

F-Labeled Cyclized α-Melanocyte-Stimulating Hormone Derivatives for Imaging Human Melanoma Xenograft with Positron Emission Tomography.

Since metastatic melanoma is deadly, early diagnosis thereof is crucial for managing the disease. We recently developed α-melanocyte-stimulating hormone (αMSH) derivatives, [Ga]Ga-CCZ01048 and [F]CCZ01064, that target the melanocortin 1 receptor (MC1R) for mouse melanoma imaging. In this study, we aim to evaluate [F]CCZ01064 as well as a novel dual-ammoniomethyl-trifluoroborate (AmBF) derivative, [F]CCZ01096, for targeting human melanoma xenograft using μPET imaging.

Functionally Versatile and Highly Stable Chelator for In and Lu: Proof-of-Principle Prostate-Specific Membrane Antigen Targeting.

Here, we present the synthesis and characterization of a new potentially nonadentate chelator Hpypa and its bifunctional analogue Bupypa-C7-NHS conjugated to prostate-specific membrane antigen (PSMA)-targeting peptidomimetic (Glu-urea-Lys). Hpypa is very functionally versatile and biologically stable. Compared to the conventional chelators (e.

Non-invasive Use of Positron Emission Tomography to Monitor Diethyl maleate and Radiation-Induced Changes in System x Activity in Breast Cancer.

Purpose: The system x transporter is upregulated in cancer cells in response to oxidative stress (OS). 5-[F]fluoroaminosuberic acid ([F]FASu) has been reported as a novel positron emission tomography (PET) imaging agent, targeting system x. The goal of this study was to evaluate the utility of [F]FASu in monitoring cellular response to diethyl maleate (DEM) and radiation-induced OS fluctuations.

Enhancing Treatment Efficacy of Lu-PSMA-617 with the Conjugation of an Albumin-Binding Motif: Preclinical Dosimetry and Endoradiotherapy Studies.

We designed and evaluated a novel albumin-binder-conjugated Lu-PSMA-617 derivative, Lu-HTK01169, with an extended blood retention time to maximize the radiation dose delivered to prostate tumors expressing prostate-specific membrane antigen (PSMA). PSMA-617 and HTK01169 that contained N-[4-( p-iodophenyl)butanoyl]-Glu as an albumin-binding motif were synthesized using the solid-phase approach. Binding affinity to PSMA was determined by in vitro competition-binding assay.

Effects of adding an albumin binder chain on [Lu]Lu-DOTATATE.

Introduction: [Lu]Lu-DOTATATE peptide receptor radionuclide therapy is used for treatment of neuroendocrine tumours. We investigated whether prolonging blood residence time of [Lu]Lu-DOTATATE with albumin binders could increase tumour accumulation and tumour-to-kidney ratios for improved therapeutic efficacy.

Methods: DOTATATE and its derivatives with an albumin-binder motif (GluAB-DOTATATE and AspAB-DOTATATE) were prepared by solid-phase peptide synthesis.

Monosodium Glutamate Reduces Ga-PSMA-11 Uptake in Salivary Glands and Kidneys in a Preclinical Prostate Cancer Model.

We evaluated the ability of monosodium glutamate (MSG) to reduce salivary and kidney uptake of a prostate-specific membrane antigen (PSMA) radioligand without affecting tumor uptake. LNCaP tumor-bearing mice were intraperitoneally injected with MSG (657, 329, or 164 mg/kg) or phosphate-buffered saline (PBS). Fifteen minutes later, the mice were intravenously administered Ga-PSMA-11.

Technical Note: Development of a phantom for dosimetric comparison of murine micro-CT protocols with optically stimulated luminescent dosimeters.

Purpose: This work aims to evaluate the utility and accuracy of a mouse-like phantom and optically stimulated luminescent dosimeters (OSLDs) in measuring dose delivered to the body and lung of mice undergoing micro-CT imaging.

Methods: A phantom with two cavities for NanoDot OSLDs (Landauer, Inc., Greenwood, IL) was designed and constructed using acrylic to model the mouse body and polyurethane foam to obtain an approximate lung tissue dose.

Effects of Linker Modification on Tumor-to-Kidney Contrast of Ga-Labeled PSMA-Targeted Imaging Probes.

Ga-PSMA-11 is currently the most popular prostate-specific membrane antigen (PSMA) radioligand used in the clinic to detect prostate cancer and metastases. However, the high uptake of Ga-PSMA-11 in kidneys can create halo-artifacts resulting in lower detection sensitivity for lesions adjacent to the kidneys. In this study, we developed two Ga-labeled PSMA-targeted tracers, Ga-HTK01166 and Ga-HTK01167, based on Ga-PSMA-617 with the goal of improving tumor-to-kidney ratio compared to Ga-PSMA-11.

Melanoma Imaging Using F-Labeled α-Melanocyte-Stimulating Hormone Derivatives with Positron Emission Tomography.

Melanocortin 1 receptor (MC1R) is specifically expressed in the majority of melanomas, a leading cause of death related to skin cancers. Accurate staging and early detection is crucial in managing melanoma. Based on the α-melanocyte-stimulating hormone (αMSH) sequence, MC1R-targeted peptides have been studied for melanoma imaging, predominately for use with single-photon emission computed tomography, with few attempts made for positron emission tomography (PET).

p-NO-Bn-Hneunpa and Hneunpa-Trastuzumab: Bifunctional Chelator for Radiometalpharmaceuticals and In Immuno-Single Photon Emission Computed Tomography Imaging.

Potentially nonadentate (NO) bifunctional chelator p-SCN-Bn-Hneunpa and its immunoconjugate Hneunpa-trastuzumab for In radiolabeling are synthesized. The ability of p-SCN-Bn-Hneunpa and Hneunpa-trastuzumab to quantitatively radiolabel InCl at an ambient temperature within 15 or 30 min, respectively, is presented. Thermodynamic stability determination with In, Bi, and La resulted in high conditional stability constant (pM) values.

Design, synthesis and evaluation of F-labeled cationic carbonic anhydrase IX inhibitors for PET imaging.

Carbonic anhydrase IX (CA-IX) is a marker for tumor hypoxia, and its expression is negatively correlated with patient survival. CA-IX represents a potential target for eliminating hypoxic cancers. We synthesized fluorinated cationic sulfonamide inhibitors 1-3 designed to target CA-IX.