# Molecular Imaging with \({}^{68}\)Ga Radio-Nanomaterials: Shedding Light on Nanoparticles
## 2 \({}^{68}\)Gallium
### Small Molecule Clinical Applications of \({}^{68}\)Ga  
Generator-based \({}^{68}\)Ga production offers a cost-effective alternative to cyclotrons and reactors. \({}^{68}\)Ga/\({}^{68}\)Ge generators allow relatively inexpensive clinical PET studies in facilities where cyclotron-produced isotopes are hard to access or unavailable. Moreover, benchtop generators can be placed in the bench of a simple synthesis module; hence, space required is insignificant in comparison with a cyclotron. Accordingly, facile and rapid production of \({}^{68}\)Ga has highly promoted its use in molecular imaging [34]. Availability of commercial generator systems and efficient purification implementations have focused the attention of clinicians on \({}^{68}\)Ga. Favorable coordination chemistry that eases coupling to small biomolecules and gallium's affinity towards tumor tissue (it has been used as chemotherapy agent) impulse \({}^{68}\)Ga as a potential alternative to \({}^{18}\)F- and \({}^{11}\)C-PET radiopharmaceuticals. Many \({}^{68}\)Ga complexes have been applied in nuclear medicine [22; 35]. \({}^{68}\)Ga-EDTA was used to study blood-brain barrier integrity and renal function [36; 37]. \({}^{68}\)Ga-citrate has been utilized to image infection in animal models and human patients [38; 39]. \({}^{68}\)Ga-phosphonate complexes have served as bone metastases trackers in small animal models [40; 41]. A derivative of tris(salicylaldimine), Tris(4,6-dimethoxysalcidylalimine)-N,N\({}^{\prime}\)-bis(3-aminopropyl)-N,N\({}^{\prime}\)-ethylenediamine (BAPEN), may be used as cardiac function radiotracer when radiolabeled with \({}^{68}\)Ga, forming \({}^{68}\)Ga-BAPEN [42; 43], \({}^{68}\)Ga-radiolabeled macroaggregated albumin (\({}^{68}\)Ga-MAA) has been used for lung function and perfusion assessment [44; 45; 46].  
As physical half-life of \({}^{68}\)Ga matches the biological half-life of numerous peptides and small molecules, the synergy of both seems a feasible approach to tackle the tracking of different biological phenomena. Somatostatin analog peptide use prevails in the literature. \({}^{68}\)Ga-DOTA-NOC, consisting of \({}^{68}\)Ga-DOTA (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid) complex conjugated to the somatostatin analog 1 (1-Na13-octreotide, NOC) has been used for the detection of a broad range of tumor types and their metastases, as for example parotid basal cell adenoma, medulloblastoma, neuroblastoma and bronchial carcinoids [47; 48; 49; 50]. Another complex using a different somatostatin analog (Tyr3-octreotate, TATE), \({}^{68}\)Ga-DOTA-TATE has also been used in several tumor-type detection and is part of ongoing clinical trials for metastatic castration-resistant prostate cancer diagnostics [51; 52]. Edotreotide (TOC), with a special affinity for type 2 somatostatin receptors has also been used combined with \({}^{68}\)Ga-DOTA (\({}^{68}\)Ga-DOTA-TOC) to diagnose cancerous lesions [53; 54; 55]. Bombesin, which is a peptide found in the intrinsic nerves of the gastrointestinal tract, has also been used in conjunction with \({}^{68}\)Ga to diagnose tumor lesions targeting gastrin-releasing peptide receptors [56; 57]. Polate conjugates have also been employed to create targeted \({}^{68}\)Ga-based complexes for ovarian cancer detection [58].  
\({}^{68}\)Ga-Pentixafor, composed by a synthetic pentapeptide that targets the chemokine receptor type 4 (CXCR4) and DOTA chelating \({}^{68}\)Ga, has been used to diagnose prostate cancer in a PC-3 prostate cancer xenograft mouse model [59]. This radiotracer has also been used for the detection of CXCR in atherosclerotic plaques [60; 61]; for neuroendocrine tumor detection; and is currently undergoing clinical trials in diagnosis of neuroendocrine tumors [62].