Conventional cancer treatment modalities have several limitations including lack 
of sufficient efficacy, serious untoward toxicity, as well as innate and 
acquired drug resistance. In contrast, targeted imaging agents can identify 
patients with receptors overexpressed on the surface of cancer cells, thus 
allowing appropriate selection of patients for personalized treatment with a 
desirable targeted therapeutic. The folate receptor (FR) has been identified as 
a new molecularly targeted entity, which is highly overexpressed on the surface 
of a spectrum of solid tumor cells, including ovarian, kidney, lung, brain, 
endometrial, colorectal, pancreatic, gastric, prostate, testicular, bladder, 
head and neck, breast, and non-small cell lung cancer. Folic acid conjugation is 
a novel approach for targeting FR-expressing tissues for personalized treatment. 
With the development of FRα-targeted therapies comes a concomitant prerequisite 
for reliable methods for the quantification of FRα tissue expression. Therefore, 
attaching a radioactive probe to folic acid to target diseased tissue has become 
a novel and powerful imaging technique. Currently available diagnostic tools 
frequently require invasive surgical biopsy. In contrast, the noninvasive 
single-photon emission computed tomography-based companion imaging agent, 
(99m)Tc-etarfolatide ((99m)Tc-EC20), is in development for use as a companion 
diagnostic with the FRα-targeted folate conjugate, vintafolide (EC145), to 
identify patients whose tumors express FRα. Vintafolide is a folic acid 
conjugate of Vinca alkaloid (desacetylvinblastine hydrazide) that targets 
FRα-expressing tumors, thereby disrupting microtubule polymerization. 
(99m)Tc-etarfolatide is taken up by FR-positive tumors and allows for 
noninvasive, whole-body monitoring of FRα expression status throughout 
treatment. The combination of vintafolide plus etarfolatide has been evaluated 
in three Phase 2 studies for the treatment of various solid tumors, including 
ovarian, endometrial, peritoneal, and platinum-resistant ovarian cancer, as well 
as lung cancer. Patients with FR-positive tumors, as identified by etarfolatide 
uptake, have had better clinical outcomes than patients with FR-negative tumors, 
indicating the potential of etarfolatide as a companion biomarker for predicting 
vintafolide response. Targeted therapies combined with a reliable companion 
diagnostic test represent a novel approach toward efficient personalized 
medicine for malignant and nonmalignant disorders. Furthermore, the recent 
availability of the crystal structures of FRα and FRβ in complex with folates 
and antifolates forms a realistic basis for the rational design and 
implementation of novel FR-targeted drugs for the treatment of cancer and 
inflammatory disorders.