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Sorbitol as a Polar Pharmacological Modifier to Enhance the Hydrophilicity of ^99mTc-Tricarbonyl-Based Radiopharmaceuticals.

ABSTRACT: The organometallic technetium-99m tricarbonyl core, [^99mTc][Tc(CO)₃(H₂O)₃]⁺, is a versatile precursor for the development of radiotracers for single photon emission computed tomography (SPECT). A drawback of the ^99mTc-tricarbonyl core is its lipophilicity, which can influence the pharmacokinetic properties of the SPECT imaging probe. Addition of polar pharmacological modifiers to ^99mTc-tricarbonyl conjugates holds the promise to counteract this effect and provide tumor-targeting radiopharmaceuticals with improved hydrophilicities, e.g., resulting in a favorable fast renal excretion in vivo. We applied the "Click-to-Chelate" strategy for the assembly of a novel ^99mTc-tricarbonyl labeled conjugate made of the tumor-targeting, modified bombesin binding sequence [Nle¹⁴]BBN(7-14) and the carbohydrate sorbitol as a polar modifier. The ^99mTc-radiopeptide was evaluated in vitro with PC-3 cells and in Fox-1^nu mice bearing PC-3 xenografts including a direct comparison with a reference conjugate lacking the sorbitol moiety. The glycated ^99mTc-tricarbonyl peptide conjugate exhibited an increased hydrophilicity as well as a retained affinity toward the Gastrin releasing peptide receptor and cell internalization properties. However, there was no significant difference in vivo in terms of pharmacokinetic properties. In particular, the rate and route of excretion was unaltered in comparison to the more lipophilic reference compound. This could be attributed to the intrinsic properties of the peptide and/or its metabolites. We report a novel glycated (sorbitol-containing) alkyne substrate for the "Click-to-Chelate" methodology, which is potentially of general applicability for the development of ^99mTc-tricarbonyl based radiotracers displaying an enhanced hydrophilicity.

SUBMITTER: Giammei C

PROVIDER: S-EPMC7321340 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Sorbitol as a Polar Pharmacological Modifier to Enhance the Hydrophilicity of 99mTc-Tricarbonyl-Based Radiopharmaceuticals.

Giammei Carolina C Balber Theresa T Benčurová Katarina K Cardinale Jens J Berroterán-Infante Neydher N Brandt Marie M Jouini Nedra N Hacker Marcus M Mitterhauser Markus M Mindt Thomas L TL

Molecules (Basel, Switzerland) 20200609 11

The organometallic technetium-99m tricarbonyl core, [99mTc][Tc(CO)3(H2O)3]+, is a versatile precursor for the development of radiotracers for single photon emission computed tomography (SPECT). A drawback of the 99mTc-tricarbonyl core is its lipophilicity, which can influence the pharmacokinetic properties of the SPECT imaging probe. Addition of polar pharmacological modifiers to 99mTc-tricarbonyl conjugates holds the p ...[more]

PMID: 32527027

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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

Sorbitol as a Polar Pharmacological Modifier to Enhance the Hydrophilicity of ^99mTc-Tricarbonyl-Based Radiopharmaceuticals.

Publications

Sorbitol as a Polar Pharmacological Modifier to Enhance the Hydrophilicity of <sup>99m</sup>Tc-Tricarbonyl-Based Radiopharmaceuticals.

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