**1. Introduction**

Thyroid cancer (TC) is one of the most common cancer types and its occurrence has been rapidly increasing over the last several years [1]. TC represents around 2–2.3% of new cancer cases and 0.2–0.4% of deaths from all cancer types [2,3]. In 2021, the USA may have approximately 44,280 new cases of TC and about 2200 deaths [2]. Around 90,000 new cases along with 6800 deaths were estimated in 2015 in China [2]. By 2030, TC is anticipated

**Citation:** Jin, Y.; Liu, B.; Younis, M.H.; Huang, G.; Liu, J.; Cai, W.; Wei, W. Next-Generation Molecular Imaging of Thyroid Cancer. *Cancers* **2021**, *13*, 3188. https://doi.org/ 10.3390/cancers13133188

Academic Editors: Fabio Medas and Pier Francesco Alesina

Received: 4 May 2021 Accepted: 22 June 2021 Published: 25 June 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

to become the second-most common type of cancer in females and the ninth in males [3]. 90–95% of cases present either papillary TC (PTC) or follicular TC (FTC), both of which originate from follicular cells in the thyroid and can be referred to as differentiated TC (DTC) [1].

In DTC, the thyroid retains the ability to absorb and store nearly all of the iodine in the whole body, providing the rationale for combined therapeutics with thyroidectomy and 131I (a beta-emitting radioisotope of iodine) therapy [4]. A total or near-total thyroidectomy removes all or most of the thyroid and DTC tissue, facilitating DTC control and the subsequent 131I ablation, adjuvant therapy, or therapy for DTCs [5]. The 131I tends to concentrate in remnant thyroid tissue, latent DTC foci, and metastatic DTC lesions. The radiation can damage the remnant thyroid tissue and DTC cells, helping DTC re-staging and improving DTC prognosis [5,6]. Unfortunately, within 10 years of an initial thyroidectomy, local recurrence and distant metastases take place in approximately 10–20% of DTCs. Notwithstanding 131I management, only one-third of DTCs could be regarded as having shown "complete response" with the remaining DTCs refractory to 131I (i.e., radioiodine refractory DTC, RR-DTC) having a poor prognosis [7].

Two less common types of TC are medullary TC (MTC) and anaplastic TC (ATC), accounting for <5% of all TC cases. Notably, however, 50–80% of MTCs show widespread metastasis at the initial diagnosis, with a five-year survival rate of 38% [8]. Furthermore, ATC is tremendously aggressive with its median overall survival of less than one year [8,9]. Thus, it is necessary to find latent lesions, precisely evaluate the grade of malignancy, adopt the most effective therapeutics, and take precautions against local recurrence or distant metastasis on time.

Traditional diagnosis methods include thyroid physical exams, blood tests (for testing biomarkers such as thyroglobulin and calcitonin), ultrasound imaging (for helping determine whether a thyroid nodule or lymph node is likely to be benign or cancerous), and other imaging tests such as CT and MRI (for TC staging and determining TC spread) [5]. In recent decades, molecular imaging (MI) has become an increasingly popular approach, applying radionuclides or artificially modified molecules to assist clinicians in locating biomarkers, potential therapeutic targets, or describing signaling pathways [10,11]. These targets play a vital role in the diagnosis and management of TC, allowing for characterization and quantification of the molecular composition of tumor tissues [12]. MI has been shown to improve diagnosis of TC, personalized management, and long-term predictive prognosis index [13]. Moreover, MI is crucial to actualizing multimodality-based theranostic strategies for TCs [14].

Over the past decade, significant progress has been made in the application of MI to TC. For instance, nanobodies and aptamers have been used to elucidate the bio-features of TC. These tracers show an antigen-binding ability resembling that of traditional antibodies [15–18]. Furthermore, immuno-single photon emission computerized tomography (immunoSPECT) and immuno-positron emission tomography (immunoPET) have encouraged the development of new theranostic methods intended for complex clinical settings, particularly for the RR-DTCs or ATCs [19]. These methods provide opportunities for obtaining deep insights into the pathogenesis of TC and as well as novel therapeutic targets for TC. Indeed, the discovery and translation of new probes enabling precise theranostics of TC are urgently needed, especially for RR-DTCs and ATCs.

Primary references are mainly derived from PubMed (available before 7 June 2021), comprehensively including the pivotal evidence in the field. In this review, transporterbased platforms are updated, and newer tracers like aptamer-, peptide-, antibody-, nanobody-, and nanoparticle-based platforms for TC are summarized. We highlight some of the potentially translatable probes in the current review. We also outline how these emerging strategies may potentially improve clinical practice.
