Dataset Information

Synthesis of Radiolabeled Technetium- and Rhenium-Luteinizing Hormone-Releasing Hormone (^99mTc/Re-Acdien-LHRH) Conjugates for Targeted Detection of Breast Cancer Cells Overexpressing the LHRH Receptor.

ABSTRACT: Currently, ^186/188Re and ^99mTc are widely used radionuclides for cancer detection and diagnosis. New advancements in modalities and targeting strategies of radiopharmaceuticals will provide an opportunity to enhance imagery and detection of smaller colonies of cancer cells while lowering false-positive diagnoses. To understand the chemistry of agents derived from fac-[^99mTc(CO)₃(H₂O)₃]⁺ species, the nonradioactive [Re(CO)₃(H₂O)₃]⁺ analogue was used. We have designed and synthesized Re-Acdien-LHRH, Re-Acdien-peg-LHRH, and a radiolabeled ^99mTc-Acdien-LHRH (rhenium- and technetium-luteinizing hormone-releasing hormone) conjugates using a tridentate linker to detect cancers overexpressing the LHRH receptor. Re-Acdien-LHRH and Re-Acdien-peg-LHRH were synthesized from non-PEGylated and PEGylated LHRH-Acdien, respectively. Cellular uptake of the compounds ^99mTc-Acdien-LHRH, Re-Acdien-LHRH, and Re-Acdien-peg-LHRH was found to be significantly enhanced compared to that of untargeted ^99mTc alone and unlabeled [Re(CO)₃(H₂O)₃]⁺. In addition, the conjugate compounds showed no difference in cellular toxicity compared to untargeted ^99mTc alone or unlabeled [Re(CO)₃(H₂O)₃]⁺. Further, a competition assay using LHRH indicated selective targeting of Re-Acdien-peg-LHRH toward the LHRH receptor (p < 0.05) compared to that of [Re(CO)₃(H₂O)₃]⁺ alone. Together, our data show the design paradigm and synthesis of targeting radionuclides using the LHRH peptide. Our data suggests that utilizing the LHRH peptide can lead to selective targeting and diagnosis of breast cancers expressing the LHRH receptor.

SUBMITTER: Calderon LE

PROVIDER: S-EPMC7841779 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Synthesis of Radiolabeled Technetium- and Rhenium-Luteinizing Hormone-Releasing Hormone (99mTc/Re-Acdien-LHRH) Conjugates for Targeted Detection of Breast Cancer Cells Overexpressing the LHRH Receptor.

Calderon Lindsay E LE Black Carrie A CA Rollins Joseph D JD Overbay Brittany B Shiferawe Semekidus S Elliott Andrew A Reitz Sara S Liu Shu S Li Junling J Ng Chin K CK Ndinguri Margaret W MW

ACS omega 20210108 3

Currently, 186/188Re and 99mTc are widely used radionuclides for cancer detection and diagnosis. New advancements in modalities and targeting strategies of radiopharmaceuticals will provide an opportunity to enhance imagery and detection of smaller colonies of cancer cells while lowering false-positive diagnoses. To understand the chemistry of agents derived from fac-[99mTc(CO)3(H2O)3]+ species, the nonradioactive [Re(C ...[more]

PMID: 33521425

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Project description:A pentapeptide macrocyclic ligand, KYCAR (lysyl-tyrosyl-cystyl-alanyl-arginine), has been designed as a potential chelating ligand for SPECT imaging and therapeutic in vivo agents. This study shows the synthesis and characterization of KYCAR complexes containing nonradioactive rhenium, 99mTc, or 188Re. The metal complexes were also biologically evaluated to determine in vivo distribution in healthy mice. The overall goals of this project were (1) to synthesize the Tc/Re pentapeptide complexes, (2) to identify spectroscopic methods for characterization of syn versus anti rhenium peptide complexes, (3) to analyze the ex vivo stability, and (4) to assess the biological properties of the [99mTc]TcO-KYCAR and [188Re]ReO-KYCAR complexes in vivo. Details on these efforts are provided below.MethodsNatRe/99mTc/188ReO-KYCAR complexes were synthesized, and macroscopic species were characterized via HPLC, IR, NMR, and CD. These characterization data were compared to the crystallographic data of ReO-KYC to assist in the assignment of diastereomers and to aid in the determination of the structure of the complex.ResultsThe radiometal complexes were synthesized with high purity (>95%). HPLC, IR, NMR and CD data on the macroscopic natReO-KYCAR complexes confirm the successful complexation as well as the presence of two diastereomers in syn and anticonformations. Tracer level complexes show favorable stabilities ex vivo for 2+ h.ConclusionMacroscopic metal complexes form diastereomers with the KYCAR ligand; however, this phenomenon is not readily observed on the tracer level due to the rapid interconversion. It was determined through pKa measurements that the macroscopic natReO-KYCAR complex is 0 at physiological pH. The [99mTc]TcO-KYCAR is stable in vitro while the [188Re]ReO-KYCAR shows 50% decomposition in PBS and serum. Biologically, the tracer level complexes clear through the hepatobiliary pathway. Some decomposition of both tracers is evident by uptake in the thyroid and stomach.

Project description:PurposeSentinel lymph node (SLN) biopsy has proven to reliably stage the clinically negative neck in early-stage oral squamous cell carcinoma (OSCC). [99mTc]Tc-tilmanocept may be of benefit in OSCC with complex lymphatic drainage patterns and close spatial relation to SLNs.MethodsA prospective within-patient evaluation study was designed to compare [99mTc]Tc-tilmanocept with [99mTc]Tc-nanocolloid for SLN detection. A total of 20 patients with early-stage OSCC were included, who underwent lymphoscintigraphy with both tracers. Both lymphoscintigraphic images of each patient were evaluated for SLN detection and radiotracer distribution at 2-4 h post-injection.ResultsThe injection site's remaining radioactivity was significantly lower for [99mTc]Tc-tilmanocept (29.9%), compared with [99mTc]Tc-nanocolloid (60.9%; p < 0.001). Radioactive uptake in SLNs was significantly lower for [99mTc]Tc-tilmanocept (1.95%) compared with [99mTc]Tc-nanocolloid (3.16%; p = 0.010). No significant difference was seen in SLN to injection site ratio in radioactivity between [99mTc]Tc-tilmanocept (0.066) and [99mTc]Tc-nanocolloid (0.054; p = 0.232). A median of 3.0 and 2.5 SLNs were identified with [99mTc]Tc-tilmanocept and [99mTc]Tc-nanocolloid, respectively (p = 0.297). Radioactive uptake in higher echelon nodes was not significantly different between [99mTc]Tc-tilmanocept (0.57%) and [99mTc]Tc-nanocolloid (0.86%) (p = 0.052). A median of 2.0 and 2.5 higher echelon nodes was identified with [99mTc]Tc-tilmanocept and [99mTc]Tc-nanocolloid, respectively (p = 0.083).Conclusion[99mTc]Tc-tilmanocept had a higher injection site clearance, but at the same time a lower uptake in the SLN, resulting in an SLN to injection site ratio, which was not significantly different from [99mTc]Tc-nanocolloid. The relatively low-radioactive uptake in SLNs of [99mTc]Tc-tilmanocept may limit intraoperative detection of SLNs, but can be overcome by a higher injection dose.

Dataset Information

Synthesis of Radiolabeled Technetium- and Rhenium-Luteinizing Hormone-Releasing Hormone (^99mTc/Re-Acdien-LHRH) Conjugates for Targeted Detection of Breast Cancer Cells Overexpressing the LHRH Receptor.

Publications

Synthesis of Radiolabeled Technetium- and Rhenium-Luteinizing Hormone-Releasing Hormone (<sup>99m</sup>Tc/Re-Acdien-LHRH) Conjugates for Targeted Detection of Breast Cancer Cells Overexpressing the LHRH Receptor.

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